Abstract

The mechanisms by which RNA acts in the DNA damage response (DDR), specifically in the repair of DNA double-strand breaks (DSBs), are emerging as multifaceted and complex. Different RNA species, including but not limited to; microRNA (miRNA), long non-coding RNA (lncRNA), RNA:DNA hybrid structures, the recently identified damage-induced lncRNA (dilncRNA), damage-responsive transcripts (DARTs), and DNA damage-dependent small RNAs (DDRNAs), have been shown to play integral roles in the DSB response. The diverse properties of these RNAs, such as sequence, structure, and binding partners, enable them to fulfil a variety of functions in different cellular contexts. Additionally, RNA can be modified post-transcriptionally, a process which is regulated in response to cellular stressors such as DNA damage. Many of these mechanisms are not yet understood and the literature contradictory, reflecting the complexity and expansive nature of the roles of RNA in the DDR. However, it is clear that RNA is pivotal in ensuring the maintenance of genome integrity. In this review, we will discuss and summarise recent evidence which highlights the roles of these various RNAs in preserving genomic integrity, with a particular focus on the emerging role of RNA in the DSB repair response.

The DNA damage response and double-strand break repair

Our genome is constantly exposed to both exogenous and endogenous genomic threats, such as ionising radiation (IR), ultraviolet radiation (UV), X-rays, reactive oxygen species (ROS) and stalled replication forks, which can lead to a variety of different DNA lesions. These lesions include DNA cross-links, adducts, mismatches, and strand breaks. DNA damage can occur at any point in the genome, and can have detrimental effects on genomic integrity, if unrepaired [1]. In particular, double-strand breaks (DSBs) are considered to be one of the most harmful forms of DNA damage, impairing processes such as replication and transcription, potentially leading to chromosomal translocations, mutations, and cell death. In order to repair genomic insults such as DSBs, the cell employs a complex recognition, signalling, and repair network known as the DNA damage response (DDR). The cell possesses two key pathways for DSB repair, homologous recombination (HR) and non-homologous end joining (NHEJ) [2–5].

HR is an active repair pathway in the late S-phase and G2 phase of the cell cycle, when a sister chromatid repair template with sufficient homology is present. HR requires extensive 5′→3′ end resection generating 3′ single-stranded DNA overhangs. The MRN (MRE11–RAD50–NBS1) complex, CtIP, an interacting partner and licensing factor, and BRCA1 promote end resection. MRE11 nicks in close proximity to the DSB and resects in the 3′→5′ direction. 5′→3′ exonucleases, EXO1 and Dna2, are recruited by the MRN complex and digest away from the break. Dna2 resection activity requires BLM to unwind the DNA duplex to provide a resection substrate, and replication protein A (RPA) binds the 3′ overhang ssDNA generated. BRCA2 facilitates RAD51 displacement of RPA and the loading of RAD51 on to the ssDNA. The RAD51-ssDNA nucleofilament then searches for homology and invades the duplex, resulting in the creation of a D-loop structure which can be resolved in a crossover or non-crossover event [2–,8](Figure 1).

NHEJ and HR are two key pathways for the repair of DSBs

Figure 1
NHEJ and HR are two key pathways for the repair of DSBs

The HR pathway of repair involves initial extensive end resection and end processing, RPA binding followed by RAD51 loading, search for a homologous sequence, strand invasion, and resolution. Other proteins involved in HR repair include: the MRN complex, CtIP, BRCA1 and 2, Exo1, Dna2, and BLM. In contrast, in the NHEJ pathway of DSB repair, end resection is prevented, and the break ends require very minimal processing. DNA-PKc, Ku, Lig4, and XRCC4 are some of the proteins known to participate in NHEJ [8]. Image created using Biorender.

Figure 1
NHEJ and HR are two key pathways for the repair of DSBs

The HR pathway of repair involves initial extensive end resection and end processing, RPA binding followed by RAD51 loading, search for a homologous sequence, strand invasion, and resolution. Other proteins involved in HR repair include: the MRN complex, CtIP, BRCA1 and 2, Exo1, Dna2, and BLM. In contrast, in the NHEJ pathway of DSB repair, end resection is prevented, and the break ends require very minimal processing. DNA-PKc, Ku, Lig4, and XRCC4 are some of the proteins known to participate in NHEJ [8]. Image created using Biorender.

The critical difference between HR and NHEJ pathway choice is the requirement of end resection for HR, and the prevention of end resection for NHEJ, with end processing being very minimal in the NHEJ pathway in contrast to HR. Antagonism between 53BP1 (anti-resection) and BRCA1 (pro-resection), coupled with the cell cycle phase and other factors such as chromatin context and transcriptional status, helps dictate through which pathway the break is repaired [3,9]. Unlike HR, a homologous template is not a requirement for NHEJ, and NHEJ is active throughout the cell cycle [3]. Initially, Ku binds to the ends of the break, recruiting DNA-PKcs. Subsequently, nucleases and polymerases process the ends for ligation. Artemis is a 5′→3′ exonuclease and forms a complex with DNA-PK, and polymerases μ and λ act in end processing through template-independent nucleotide addition. Lig4 and XRCC4 can ligate together DNA ends of the DSB in complex with Ku, either by blunt-end ligation or following end processing [2–,8,10] (Figure 1).

RNA in DSB repair

It is emerging that RNA has many functions in the repair of DSBs [11–14]. RNA can be either coding messenger RNA (mRNA), translated into proteins, or non-coding RNA (ncRNA), not translated into protein. These ncRNA can be further divided into the classes long non-coding RNA (lncRNA, >200 bp), or small ncRNA (<200 bp) [15]. Small ncRNAs include, but are not limited to, microRNA (miRNA), and the recently identified DNA damage-dependent small RNA (DDRNA) [16]. While RNA processing mechanisms such as RNA splicing and RNA import and export from the nucleus are known to be regulated in response to DSB induction (reviewed in [17,18]); in this review we will be focussing on RNA molecules themselves as regulatory components of the DDR. In particular, we will be discussing the role of both short (miRNA and DDRNA) and long ncRNAs, RNA:DNA hybrid structures, and RNA modifications in mammalian DSB repair.

MiRNA roles in DSB repair

MiRNAs are ∼22 nucleotide small ncRNAs which have partial sequence complementarity to specific mRNAs. Ribonucleases Dicer and Drosha are responsible for miRNA processing. miRNAs are transcribed as primary transcripts (pri-miRNA) and processed firstly by Drosha and DGCR8 in the nucleus into pre-miRNA. The pre-miRNAs are then exported via Exportin-5 and Ran-GTP into the cytoplasm, where Dicer and TRBP cleave pre-miRNA into mature miRNA, which then are loaded on to Ago proteins to form the RNA-induced silencing complex (RISC) complex. MiRNAs can down-regulate the expression of mRNAs in a process known as RNA interference (RNAi) by guiding RISC to an mRNA with sequence complementarity. mRNA degradation machinery can then be recruited which either disrupts the translational machinery or degrades the target mRNA [11,19].

MiRNA processing is known to be altered in response to DSB induction. For example, Dicer and Drosha binding partners can be regulated by ATM [20–23], ATM can regulate miRNA transcription by phosphorylating transcription factors, and regulate miRNA maturation, processing, and export from the nucleus [24]. Furthermore, DGCR8 can be phosphorylated by c-Abl kinase upon DSB induction [25,26], BRCA1 can associate with Drosha [27] and bind to pri-miRNAs [20,28], and DSBs can induce p53-mediated miRNA transcriptional changes, resulting in differential expression of miRNAs [28]. Over 60% of protein-coding mRNAs are predicted to be targeted by miRNAs [20], and one miRNA can target many different genes [29]. Of these miRNAs, many are now known to play key roles in DSB repair, regulating the levels of a variety of DSB repair factors to augment the DDR to DSBs (Table 1) [11]. Examples of miRNAs regulating DSB repair factors include miR-421, miR-100, and miR-181 regulation of ATM [20,28], miR-24 and miR-138 regulation of H2AX [28,30], and miR-34 family regulation of RAD51 [31]. Furthermore, miRNAs miR-1255b, miR-148b*, and miR-193b* protect genome integrity by promoting DSB repair via the NHEJ pathway in G1, through suppression of HR factors BRCA1, BRCA2, and RAD51, preventing loss of heterozygosity (LOH) [32].

Table 1
DSB repair factors and miRNAs which target them
DSB repair proteinmiRNAReferences
H2AX miR-138
miR-24 
[30,33
ATM miR-421
miR-101
miR-100
miR-181 
[20,28,34–36
CtIP miR-130b
miR-335 
[37,38
MRE11 miR-493-5p [39
MDC1 miR-22 [40
MAD2L2 miR-890 [29
53BP1 miR-34a [41
BRCA1 miR-1255b
miR-148b*
miR-193b*
miR-182 
[32,42
BRCA2 miR-19a
miR-19b
miR-1255b
miR-148b*
miR-193b*
miR-19a-3p 
[32,43,44
RAD51 miR-1255b
miR-148b*
miR-193b*
miR-34
miR-96-5p 
[31,32,44
RAD51c miR-222 [45
DNA-PKc miR-101
miR-874-3p 
[36,44,46
Ku80 miR-526b
miR-622
miR-218-5p 
[44,47,48
Ku70 miR-502
miR-545
miR-622 
[48–50
Lig4 miR-1246
miR-4727-5p 
[51,52
XLF miR-502 [49
GSK3B miR-21 [53
DSB repair proteinmiRNAReferences
H2AX miR-138
miR-24 
[30,33
ATM miR-421
miR-101
miR-100
miR-181 
[20,28,34–36
CtIP miR-130b
miR-335 
[37,38
MRE11 miR-493-5p [39
MDC1 miR-22 [40
MAD2L2 miR-890 [29
53BP1 miR-34a [41
BRCA1 miR-1255b
miR-148b*
miR-193b*
miR-182 
[32,42
BRCA2 miR-19a
miR-19b
miR-1255b
miR-148b*
miR-193b*
miR-19a-3p 
[32,43,44
RAD51 miR-1255b
miR-148b*
miR-193b*
miR-34
miR-96-5p 
[31,32,44
RAD51c miR-222 [45
DNA-PKc miR-101
miR-874-3p 
[36,44,46
Ku80 miR-526b
miR-622
miR-218-5p 
[44,47,48
Ku70 miR-502
miR-545
miR-622 
[48–50
Lig4 miR-1246
miR-4727-5p 
[51,52
XLF miR-502 [49
GSK3B miR-21 [53

Table adapted from [11].

MiRNA-independent functions of Dicer and Drosha in DSB repair

The canonical miRNA processing functions of Dicer and Drosha have long been established, and their role in miRNA-dependent regulation of DDR factors and DSB factors has been widely studied. However, it is becoming apparent that Dicer and Drosha possess activities in the DSB response which are outside of their canonical miRNA processing roles [19]. While Dicer carries out its miRNA processing in the cytoplasm, a subset of Dicer protein (estimated to be ∼5% of the total dicer pool [54]) has been shown to localise in the nucleus, in order to mediate processing of damage-specific RNA transcripts [55]. Although the nuclear localisation of Dicer has previously been challenged [56], many studies have shown that Dicer can localise in the nucleus [57–59].

In response to DSB induction, Dicer is phosphorylated on residues S1016 and S1728/S1852, and colocalises with γH2AX in the nucleus [55]. Knockdown of Dicer or Drosha reduces foci formation of some DSB repair factors, including 53BP1 and MDC1, in response to IR, suggesting Dicer and Drosha activity is required for DSB repair factor recruitment [16,60]. These DDR foci are sensitive to treatment with RNase A, and can be rescued by re-addition of the small RNA fraction extracted from IR-treated cells, but not Dicer mutant cells. Therefore, Dicer specifically processes small RNAs which are required for DDR focus formation. Using endonuclease site-specific systems, such as the I-SceI-induced DSB system, these RNAs were further characterised as 22–23 nt RNAs originating from the site of the DSB. Synthesis of RNA from sequences surrounding the sequence-specific DSB cut sites was able to rescue 53BP1 and MDC1 foci after RNase A treatment, confirming the sequence-specific nature of the Dicer processing products [16,60]. Taken together, the data suggest that Dicer and Drosha process small RNAs, known as DDRNA, which play a role in the DDR to DSBs [16,60]. These DDRNAs have been suggested to originate from lncRNAs, which are transcribed by RNA polymerase II (RNAPII), actively recruited to the DSB site through interaction with the MRN complex [61,62], both towards and away from the break. Interestingly, the ends of the DSB break can act as promoters for RNAPII transcription [62]. Two differing models have been proposed for RNAPII-dependent transcription at DSB sites. In the first model, damage-induced lncRNA (dilncRNA) are transcribed by RNAPII phosphorylated on the C-terminal domain (CTD) at Serine 2 or 5 (S2P or S5P), a mark of active polymerase transcription. The dilncRNA are either processed by Dicer into DDRNA, or hybridise with the DDRNA, localising them to the DSB site [61]. In the second model, RNAPII is phosphorylated by the kinase c-Abl at the CTD tyrosine position 1 (Y1P) [63]. Y1P RNAPII has been shown to colocalise with γH2AX foci at the sites of promoter-associated DSBs, and is enriched at ASiSI endonuclease cut sites. This Y1P RNAPII transcribes lncRNAs at the DSB site. These lncRNAs then form RNA:DNA hybrids at the DSB site, to promote antisense transcription, production of damage-responsive transcripts (DARTs), and dsRNA production. Accordingly, treatment of cells with either RNase H (RNA:DNA hybrid specific) or RNase III (dsRNA specific) results in reduced 53BP1 foci [63]. While the two models differ slightly in mechanistic detail, it is clear that mounting evidence has underscored the role of RNAPII transcription and Dicer-dependent RNA processing at the sites of breaks in DSB repair, and more specifically in the recruitment of repair factors such as 53BP1 to DSBs. How exactly repair is coordinated by RNA at the break is as yet unclear, and interestingly, γH2AX foci were not shown to be dependent on Dicer and Drosha, which has led to the suggestion that Dicer and Drosha may act in parallel with γH2AX to recruit secondary repair factors [16,60]. It has also been suggested that DDRNA may act to promote phase separation of 53BP1 repair foci to facilitate DSB repair [62]. Together these data suggest that repair factor recruitment to DSBs requires site-specific RNA transcribed at the break [16,55,60–63].

Furthermore, Bonath et al. [64] detect short de novo transcription-dependent RNAs originating from I-PpoI-induced DSB sites in mammalian cells of predominantly 21–22 nt in length (referred to as diRNA). However these diRNA could only be detected at sites in repetitive ribosomal regions, but not unique genic or intergenic sites. In contrast, RNAPII-dependent dilncRNA synthesis was observed at both repetitive and non-repetitive sites. This suggests that RNA processing at break sites may differ depending on the genomic context of the DSB. The same study also identified different populations of diRNA, a Dicer-dependent and a Dicer-independent population. The authors also find that Drosha is not required for the production of diRNA, potentially suggesting the repair defects observed upon Drosha knockdown may be due to Drosha activity independent of diRNA/DDRNA processing. Therefore, DDRNA/diRNA production and processing may differ depending on where the DSB occurs, and further work will be required to elucidate the contribution of Dicer and Drosha to DSB repair [64].

LncRNAs: direct and indirect regulators of DSB repair

There are estimated to be tens of thousands of lncRNAs encoded in the human genome [65,66]. Aside from the lncRNAs dilncRNA and DARTs, a vast array of other lncRNAs have been implicated in the DSB response and the DDR more widely, including in chromatin organisation, cell cycle regulation, and gene expression regulation. The expression of various lncRNAs can be modulated in response to IR [67,68]. LncRNAs also bind DSB repair factors, of which examples include MALAT1, TERRA, and lincRNA-p21 lncRNAs (reviewed in [11]). In this section we will focus on a handful of specific examples of lncRNAs which have recently been implicated in the DDR, both directly, such as through binding to DNA repair proteins, and indirectly, such as by regulating translation of proteins involved in genome stability and DNA repair, highlighting the variety of mechanisms by which lncRNAs can influence repair (Figure 2).

Direct and indirect functions of lncRNAs in response to DNA damage

Figure 2
Direct and indirect functions of lncRNAs in response to DNA damage

LncRNAs can be differentially expressed or regulated upon DNA damage, and can have a wide range of functions in repair. Examples of lncRNA functions include: at the sites of breaks by recruiting or scaffolding repair factors, in cell cycle regulation, as miRNA sponges, and transcriptional or translational regulation. Image created using Biorender.

Figure 2
Direct and indirect functions of lncRNAs in response to DNA damage

LncRNAs can be differentially expressed or regulated upon DNA damage, and can have a wide range of functions in repair. Examples of lncRNA functions include: at the sites of breaks by recruiting or scaffolding repair factors, in cell cycle regulation, as miRNA sponges, and transcriptional or translational regulation. Image created using Biorender.

PRLH1 (p53-regulated lncRNA for HR repair 1) is an example of a direct regulator of DSB repair at the site of the break. PRLH1 is p53 regulated and functions in DSB repair pathway choice through its ability to bind RNF169 [69], an E3 ubiquitin ligase, a paralogue of the RNF168. The complex of PRLH1 and RNF169 competes with 53BP1 for binding to RNF168 ubiquitinated chromatin, repressing NHEJ and promoting HR. Knockdown of PRLH1 reduces RNF169 levels, suggesting PRLH1 can regulate HR-mediated DSB repair through stabilisation of RNF169 [69,70]. Consequently, overexpression of PRLH1 lncRNA can promote HR-mediated DSB repair [69,71]. LncRNA HIF-1a inhibitor at translational level (HITT) is another example of a direct DSB regulator. HITT is an ATM interactor, and is up-regulated following DSB induction by EGR1 activity in a p53-independent manner [72]. HITT can augment DSB repair via increased interaction with ATM, reducing the levels of chromatin-bound ATM after DSB induction. Mechanistically, HITT prevents ATM recruitment to DSBs through binding to ATM at the site of NBS1 interaction, blocking ATM and NBS1 association. Consequently, HITT can inhibit DNA end resection through its ability to interact with ATM. HITT has been suggested to be a mechanism of restraining ATM activity in certain cellular contexts, for example after completion of repair, as HITT is up-regulated later relative to ATM activation in the DSB response [72]. PRLH1 and HITT serve as interesting examples of how lncRNAs can be differentially expressed after DSB induction, and can interact directly with key repair proteins such as RNF169 and ATM to regulate DSB repair.

LncRNAs can also act as indirect regulators of DNA repair. One such example of an indirect DNA repair regulator is ncRNA activated by DNA damage (NORAD) [65,73]. NORAD is an lncRNA implicated in preservation of genomic stability, for example via its PUMILIO regulation. PUMILIO proteins are a family of RNA-binding proteins required for a variety of cellular processes [65,74]. PUMILIO proteins bind to mRNA 3′ UTRS in the cytoplasm, stimulating decapping and subsequently down-regulating their translation [65,74]. NORAD was identified as up-regulated in response to DNA damage by Doxorubicin, dependent on p53 [65,75]. PUMILIO proteins bind to NORAD, and are sequestered, resulting in reduced down-regulation of PUMILIO target mRNAs [74,76]. PUMILIO target RNAs shown to be altered in expression upon NORAD depletion include PARP1, BARD1, and EXO1, and other proteins involved in DNA repair, replication, and the cell cycle [65]. Indeed, knockout of NORAD results in aneuploidy and chromosomal instability, hence NORAD is required to maintain genome integrity [65,77]. Other examples of indirect regulators of DNA repair include lncRNA ANRIL, which is activated by ATM signalling after DNA damage, and influences cell cycle progression [78], and lncRNA PANDA, which is up- regulated in a p53-dependent manner after doxorubicin treatment and regulates apoptosis [79]. LncRNAs can also act indirectly in DNA repair as miRNA sponges, competing with endogenous mRNA targets to regulate gene expression, to preserve genome integrity. For example, GUARDIN can sponge miR-23a which targets TRF2 [80], and lnc-RI can compete with miR-4727-5p to regulate Lig4 [52].

These examples highlight how lncRNAs can have multifaceted roles both directly, via direct interaction with DNA repair factors at the site of DSBs, and indirectly, such as influencing transcription of DNA repair factors, cell cycle progression and apoptosis, or as miRNA sponges in the cellular response to damage induction. These and other examples are summarised in Table 2.

Table 2
Examples of lncRNAs and their functions in DNA repair
lncRNAFunctionReference
GUARDIN Sequesters miR-23a to stabilise TRF2, also scaffolds BRCA1 and BARD1, stabilising BRCA1 [80
HOTAIR Regulates miR-218 to influence radiosensitivity [81
LIRR1 Up-regulated upon X-ray IR exposure, LIRR1 overexpression decreases expression of DSB repair factors including Ku70 and Ku80 [82
MALAT1 Forms a complex with PARP1 and Lig3, which are involved in NHEJ, and is required for recruitment of Lig3 to DSB sites [83
TERRA At deprotected telomeres, TERRA binds SUV39H1 H3K9 histone methyltransferase, increasing H3K9me3 and end-to-end fusions [84,85
ANRIL Activated by ATM signalling in response to DNA damage, and is involved in cell cycle regulation [78
HITT Interacts with ATM and restrains HR-mediated DSB repair [72
DINO Interacts with and stabilises p53 in response to doxorubicin treatment [86
lincRNA-p21 Regulation of apoptosis via p53 through interaction with hnRNP-K [87,88
PCAT-1 Post-transcriptional regulation of BRCA2 [89,90
PANDA Upregulated in response to doxorubicin and regulates apoptosis [79
LINP1 Translocates from cytosol to nucleus upon IR exposure and scaffolds Ku80 and DNA-PKc [91,92
DDSR1 Interacts with BRCA1 to modulate HR [93
NORAD Sequesters PUMILIO proteins, whose target mRNAs include DNA repair and replication proteins, and cell cycle regulators [65,73–75
TODRA RAD51 regulation [94
Lnc-RI Regulates RAD51 expression by competing with miR-193a-3p, also competes with miR-4727-5p to regulate Lig4 expression [52,95
CUPID1 and CUPID2 Regulate DNA end resection [96
BGL3 Recruited to DSBs and is required for BRCA1-BARD1 accumulation at DSBs [97
lncRNAFunctionReference
GUARDIN Sequesters miR-23a to stabilise TRF2, also scaffolds BRCA1 and BARD1, stabilising BRCA1 [80
HOTAIR Regulates miR-218 to influence radiosensitivity [81
LIRR1 Up-regulated upon X-ray IR exposure, LIRR1 overexpression decreases expression of DSB repair factors including Ku70 and Ku80 [82
MALAT1 Forms a complex with PARP1 and Lig3, which are involved in NHEJ, and is required for recruitment of Lig3 to DSB sites [83
TERRA At deprotected telomeres, TERRA binds SUV39H1 H3K9 histone methyltransferase, increasing H3K9me3 and end-to-end fusions [84,85
ANRIL Activated by ATM signalling in response to DNA damage, and is involved in cell cycle regulation [78
HITT Interacts with ATM and restrains HR-mediated DSB repair [72
DINO Interacts with and stabilises p53 in response to doxorubicin treatment [86
lincRNA-p21 Regulation of apoptosis via p53 through interaction with hnRNP-K [87,88
PCAT-1 Post-transcriptional regulation of BRCA2 [89,90
PANDA Upregulated in response to doxorubicin and regulates apoptosis [79
LINP1 Translocates from cytosol to nucleus upon IR exposure and scaffolds Ku80 and DNA-PKc [91,92
DDSR1 Interacts with BRCA1 to modulate HR [93
NORAD Sequesters PUMILIO proteins, whose target mRNAs include DNA repair and replication proteins, and cell cycle regulators [65,73–75
TODRA RAD51 regulation [94
Lnc-RI Regulates RAD51 expression by competing with miR-193a-3p, also competes with miR-4727-5p to regulate Lig4 expression [52,95
CUPID1 and CUPID2 Regulate DNA end resection [96
BGL3 Recruited to DSBs and is required for BRCA1-BARD1 accumulation at DSBs [97

R-loops and RNA:DNA hybrids in DSB repair

R-loops are composed of an RNA:DNA hybrid and a single strand of DNA, forming a three-stranded structure [98,99]. R-loops and RNA:DNA hybrids can be a source of genomic instability, as they can impair the replication and transcription machinery [99], and the single-stranded DNA component of the R-loop can be vulnerable to DNA damage [100]. However, RNA:DNA hybrids and R-loops play important roles in class-switch recombination, transcription, and DNA repair, including DSB repair (reviewed in [18,99,101]). DNA:RNA hybrid induction has been observed at areas surrounding DSBs, using different sequence-specific nucleases and model systems including but not limited to; the I-PpoI system in Schizosaccharomyces pombe (S. pombe) [102] and humans [103], a fluorescently labelled catalytically inactive RNaseH1 with laser microirradiation in human cells [104,105], in AsiSI U2OS cells with GFP-RNase H1 by ChIP [63], and using the RNA:DNA hybrid specific antibody for immunoprecipitation [63,106]. RNA:DNA hybrids have been suggested to form as a result of dilncRNA synthesis and are involved in the production of DDRNA (discussed above) [63,107].

Factors which have been suggested to influence the accumulation of RNA:DNA hybrids at DSBs include the location of the break, transcriptional status at the site of the DSB, and the downstream repair pathway. RNA:DNA hybrids have been observed preferentially at DSBs in actively transcribed regions of the genome [105,106]. Using the AsiSI cell line system, Cohen et al. observed that RNA:DNA hybrids accumulate at DSBs preferentially in transcribed regions, and more modestly in untranscribed regions [100]. Similarly, Bader et al. find that high transcriptional activity generally correlates positively with hybrid formation at DSBs [108]. As Bader et al. highlighted, intergenic regions are not necessarily transcriptionally silent, and they find that transcriptional activity, but not intergenic or genic location, determines RNA:DNA hybrid formation [108]. However, RNA:DNA hybrids have been detected at some transcriptionally inactive sites, indicating that RNA:DNA hybrids have the potential to form at DSBs even in transcriptionally silent regions of the genome [103,109]. Overall, the evidence suggests transcriptional status may, at least in part, influence RNA:DNA hybrid formation or stability at DSBs.

The contribution of RNA:DNA hybrids preferentially to either HR or NHEJ-mediated DSB repair is unclear. There is evidence to suggest that RNA:DNA hybrids may differentially contribute HR or NHEJ DSB repair pathways. RNA:DNA hybrids have been shown to be required for the recruitment of HR repair factors to DSBs, including BRCA1, BRCA2 [103], and RAD52 [105], and numerous studies have shown that modulation of RNA:DNA hybrid formation and processing impacts HR-mediated DSB repair [100,102,103,105,110,111], suggesting a more prominent role for RNA:DNA hybrids in HR. However, in some instances RNA:DNA hybrids have been shown to form at sites repaired by both NHEJ and HR [106,108]. Drosha can promote RNA:DNA hybrid accumulation at DSBs, and Drosha depletion attenuates RNA:DNA hybrid formation, impairing both HR and NHEJ repair [106]. The intrinsically disordered protein RBM14 was shown to be required for the formation of RNA:DNA hybrids at DSB sites, and knockdown of RBM14 reduces NHEJ, implicating RNA:DNA hybrids in NHEJ-mediated DSB repair [109].

While a growing body of evidence has underscored the importance of RNA:DNA hybrids in DSB repair, a failure to process RNA:DNA hybrids at DSBs can lead to DNA damage and genome instability. This highlights that while RNA:DNA hybrids play a key role in repair, they must be tightly regulated. For example, Senataxin, an RNA:DNA helicase, is recruited to RNA:DNA hybrids at DSBs in transcriptionally active regions, but not intergenic or transcriptionally silent regions. Senataxin acts to prevent potential translocations at break ends in transcriptionally active loci, possibily by resolving RNA:DNA hybrids [100]. Furthermore, depletion of Senataxin or RNA:DNA hybrid processing enzymes RNase H1 and H2 in Saccharomyces cerevisiae (S. cerevisiae) results in cell cycle arrest and DNA damage [112]. While transient RNA:DNA hybrids are required to regulate end resection in S. pombe, the depletion of RNase H1, and subsequent lack of RNA:DNA hybrid removal, impairs RPA loading to ssDNA at the DSB site [102]. BRCA2 also recruits RNase H2 to regulate RNA:DNA hybrid levels at DSBs [56]. HNRNPD, an RNA-binding protein whose knockdown impairs HR, is required to resolve RNA:DNA hybrids in order to facilitate DNA end resection [111]. Moreover, EXOSC10, an RNA exosome subunit, processes RNA:DNA hybrids which occur at DSBs from dilncRNAs, necessary for end-resection regulation and RPA binding to ssDNA for HR-mediated DSB repair [107,110,113]. This suggests that while RNA:DNA hybrids are an important component of repair, their regulation and timely removal by ribonucleases such as Senataxin, EXOSC10, and RNase H enzymes, is necessary for proper DSB repair.

RNA:DNA hybrids play a key role in DSB repair, although their generation and regulation must be carefully controlled in order to preserve genome integrity. Data suggest that the role of RNA:DNA hybrids may be context specific, potentially depending on chromatin context, transcriptional status, and cell cycle phase [14].

Looking ahead: RNA modifications and the DDR. A role for RNA modifications in DSB repair?

It is now understood that RNA itself, much like DNA and proteins, can be modified post-transcriptionally. These RNA modifications possess the ability to alter a diverse array of cellular processes, including cell cycle progression and apoptosis, by altering the stability and structure of RNAs, and protein–RNA interactions. Modifications of RNA include; N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 2′-O-methylation (2′-OMe), and pseudouridine (Ψ), however over 150 RNA modifications have been identified (Figure 3). Many different RNAs can be modified, such as transfer RNAs (tRNAs), ribosomal RNAs (rRNA), mRNAs, and lncRNAs [114,115]. Recently, RNA modifications have been suggested to play a role in the cellular response to DNA damage [116].

The structures of modifications which can be found in RNA

Figure 3
The structures of modifications which can be found in RNA

m6A, m1A, m5C, 2′-OMe, and Ψ are depicted. It is now understood that RNA modifications can influence the stability and structure of RNAs, alter protein–RNA interactions, and therefore regulate the functionality of many RNAs. Image created using Biorender.

Figure 3
The structures of modifications which can be found in RNA

m6A, m1A, m5C, 2′-OMe, and Ψ are depicted. It is now understood that RNA modifications can influence the stability and structure of RNAs, alter protein–RNA interactions, and therefore regulate the functionality of many RNAs. Image created using Biorender.

m6A, found in both DNA and RNA, is the most abundant internal RNA modification found in cells, and known functions include in mRNA splicing [117,118], translation [119–121], and cell cycle regulation [122,123]. The RNA m6A modification is reversible, and has several writers (the METTL3–METTL14 complex, METTL16, WTAP), and erasers (ALKBH1/3/5, and FTO) [118,124–127]. m6A has also been implicated in the cellular stress response, DNA repair, and cancer progression. LncRNA LNCAROD, which is up-regulated in HNSCC, is highly m6A modified by METTL3 and METTL14 in these samples. m6A modification stabilises LNCAROD, and LNCAROD expression correlates with poor prognosis and tumorigenicity in HNSCC [128]. In gastric cancer, m6A-associated genes were found to be dysregulated, and poor prognosis correlated with high expression of FTO and WTAP [129]. Moreover, m6A can modulate translation in acute myeloid leukemia [130], and in response to heat shock [131]. m6A demethylase FTO has also been implicated in the DDR and the stress response in mice osteoblasts, where FTO knockout led to an increase in DNA damage and apoptosis in response to genotoxic stress, suggesting a role for m6A and FTO in the cellular stress response [132]. Recent studies have found that m6A has a further role in the DDR in the repair of UV-induced DNA damage, specifically in the nucleotide excision repair (NER) pathway. The RNA m6A-modification accumulates rapidly at UV laser microirradiated sites, colocalising with the m6A writer METTL3–METTL14 complex. More generally, UVC induced m6A in a variety of transcripts, indicating a possible dual role of m6A in the UV DDR, both at the site of the damage and more globally within the cell [133,134]. m6A was found to be required for the recruitment of downstream repair factors, such as Polymerase κ (Pol κ), although DSB repair factors such as BRCA1 and 53BP1 were not dependent on the m6A writer METTL3 for recruitment to damage [133]. However, it is now understood that the m6A modification is required for the DDR to UV damage, providing proof of principle that RNA modifications can function in the DDR. A role for m6A at DSB sites is yet to be established, although m6A levels have been found to be altered in response to DSBs [127,135]. m6A and METTL3 were found to be elevated in glioma stem-like cells in response to IR, and silencing of METTL3 reduced DSB repair and enhanced the sensitivity to IR in these cells [135]. Moreover, the lncRNA pncRNA-D m6A modification levels were found to be reduced in response to IR or osmotic stress, which can induce DSBs, suggesting m6A can be modulated in response to DSBs [127].

Furthermore, m6A has been shown to be present on RNA:DNA hybrids [136,137]. Abakir et al. have shown that m6A can coordinate R-loop removal with the m6A reader, YTH-domain family member 2 (YTHDF2), contributing to genome stability [136,138]. Interestingly, this m6A modification of R-loops is not constitutive, but rather is cell cycle dependent. m6A is present on R-loops in S and G2/M phases of the cell cycle, and is reduced in the G0/G1 phases of the cell cycle [136,138]. It is not yet clear if this could impact the DDR, in particular the DSB response, but given the known role of R-loops in DSB repair [63,100,111], it implicates a further possible role for m6A in the cellular DDR.

Another RNA modification with roles in the cellular stress response is m1A. m1A is present on RNA at approximately 5–10% that of m6A, and can be found in tRNA, rRNA, and has recently been identified in mRNA and lncRNA [139–142]. m1A on various RNAs can be modulated in response to stress conditions, such as hydrogen peroxide treatment which can induce strand breaks in DNA. Interestingly, this m1A RNA modification can be reversed by ALKBH3, an enzyme with a known role in DNA repair [140]. While m1A has not been shown to be recruited to UV-microirradiation in the same manner as m6A [134] further studies may shed light on a potential role of in the DDR. However, it is important to note that there has been controversy regarding the m1A antibody, suggesting m1A peaks identified in 5′UTRs are likely the result of antibody cross-reactivity with the m7G-cap of RNA [143].

Furthermore, ADP-ribosylation, a modification known to be involved in a variety of cellular processes [144], including the repair of DSBs, has been identified as a reversible RNA modification [145]. ADP ribosylation, where an ADP-ribose group is added to a molecule, was previously only known to be present on DNA and proteins. However, Munnur et al. have identified that RNA can be ADP-ribosylated, and this modification can be removed by a variety of enzymes, including NUDT16 [145], which has recently been shown to play a role in DSB repair [146]. While RNA ADP-ribosylation has only been shown in vitro, it is interesting to speculate about its possible role in cells in the DDR, given the importance of ADP-ribosylation of DNA and protein in DSB repair and RNA biology [144,147].

Conclusion

RNAs play roles in the repair of DSBs at multiple levels. The specific features of each of the RNAs, including sequence, structure, and binding partners, enable RNA to have a wide variety of functions both at the sites of DSBs and more generally in the DDR. These roles include direct binding of repair factors both at the sites DSBs and elsewhere in the cell, post-transcriptional regulation of repair factor expression, and regulation of end resection. Furthermore, understanding how ways of altering RNA properties, such as RNA modification, can impact DNA repair will likely be an area of expanding interest. New technologies to map RNA modifications such as sequencing technologies [148] and mass spectrometry analysis tools [149] will enable the further understanding of the cellular role of RNA modifications. Elucidating the many ways in which RNA can influence DNA repair processes is of importance for understanding how RNAs can influence tumorigenesis and cancer progression, and ultimately could be targeted for cancer therapeutics [150].

Summary

  • DSBs are considered one of the most cytotoxic forms of DNA damage, and their repair is critical to preserve genomic information.

  • RNA is emerging as a key player in the DSB repair response.

  • MiRNAs, lncRNAs, RNA:DNA hybrids, dilncRNAs, DARTs, and DDRNAs act through various mechanisms, such as in transcriptional gene silencing, as scaffolds for proteins, and signalling molecules, to augment the DSB response and maintain genomic integrity.

  • Modification of RNA is emerging as a mechanism of regulation in DNA repair. We speculate RNA modifications are an area of future research in the DSB repair field.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Senior Research Fellowship by Cancer Research U.K. [grant number BVR01170 (to M.G.)]; and the Lee Placito Trust [grant number BVR01070 (to M.G.)].

Open Access

Open access for this article was enabled by the participation of University of Oxford in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.

Acknowledgements

We are grateful to all members of M.G. lab, in particular Dr Adele Alagia and Jana Terenova, for their comments and suggestions.

Abbreviations

     
  • 2′-OMe

    2′-O-methylation

  •  
  • m5C

    5-methylcytosine

  •  
  • CTD

    C-terminal domain

  •  
  • DART

    damage-responsive transcript

  •  
  • DDR

    DNA damage response

  •  
  • DDRNA

    DNA damage-dependent small RNA

  •  
  • dilncRNA

    damage-induced long non-coding RNA

  •  
  • DSB

    double-strand break

  •  
  • HITT

    HIF-1a inhibitor at translational level

  •  
  • HR

    homologous recombination

  •  
  • IR

    ionising radiation

  •  
  • lncRNA

    long non-coding RNA

  •  
  • miRNA

    microRNA

  •  
  • MRN

    MRE11–RAD50–NBS1

  •  
  • mRNA

    messenger RNA

  •  
  • m1A

    N1-methyladenosine

  •  
  • m6A

    N6-methyladenosine

  •  
  • ncRNA

    non-coding RNA

  •  
  • NHEJ

    non-homologous end joining

  •  
  • NORAD

    ncRNA activated by DNA damage

  •  
  • pri-miRNA

    primary transcript of miRNA

  •  
  • PRLH1

    p53-regulated lncRNA for HR repair 1

  •  
  • RISC

    RNA-induced silencing complex

  •  
  • RNAPII

    RNA polymerase II

  •  
  • RPA

    replication protein A

  •  
  • rRNA

    ribosomal RNA

  •  
  • tRNA

    transfer RNA

  •  
  • UV

    ultraviolet radiation

References

References
1.
Jackson
S.P.
and
Bartek
J.
(
2009
)
The DNA-damage response in human biology and disease
.
Nature
461
,
1071
1078
2.
Her
J.
and
Bunting
S.F.
(
2018
)
How cells ensure correct repair of DNA double-strand breaks
.
J. Biol. Chem.
293
,
10502
10511
[PubMed]
3.
Chapman
J.R.
,
Taylor
M.R.G.
and
Boulton
S.J.
(
2012
)
Playing the end game: DNA double-strand break repair pathway choice
.
Mol. Cell
47
,
4
,
497
510
4.
Ranjha
L.
,
Howard
S.M.
and
Cejka
P.
(
2018
)
Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes
.
Chromosoma
127
,
187
214
[PubMed]
5.
Shibata
A.
(
2017
)
Regulation of repair pathway choice at two-ended DNA double-strand breaks
.
Mutat. Res.
803-805
,
51
55
6.
Panier
S.
and
Boulton
S.J.
(
2014
)
Double-strand break repair: 53BP1 comes into focus
.
Nat. Rev. Mol. Cell Biol.
15
,
7
18
[PubMed]
7.
Bonetti
D.
,
Colombo
C.V.
,
Clerici
M.
and
Longhese
M.P.
(
2018
)
Processing of DNA ends in the maintenance of genome stability
.
Front. Genet.
9
,
390
[PubMed]
8.
Scully
R.
,
Panday
A.
,
Elango
R.
and
Willis
N.A.
(
2019
)
DNA double-strand break repair-pathway choice in somatic mammalian cells
.
Nat. Rev. Mol. Cell Biol.
20
,
698
714
[PubMed]
9.
Marini
F.
,
Rawal
C.C.
,
Liberi
G.
and
Pellicioli
A.
(
2019
)
Regulation of DNA double strand breaks processing: focus on barriers
.
Front. Mol. Biosci.
6
,
55
[PubMed]
10.
Pannunzio
N.R.
,
Watanabe
G.
and
Lieber
M.R.
(
2018
)
Nonhomologous DNA end-joining for repair of DNA double-strand breaks
.
J. Biol. Chem.
293
,
10512
10523
[PubMed]
11.
Thapar
R.
(
2018
)
Regulation of DNA double-strand break repair by non-coding RNAs
.
Molecules
23
,
2789
12.
Bader
A.S.
,
Hawley
B.R.
,
Wilczynska
A.
and
Bushell
M.
(
2020
)
The roles of RNA in DNA double-strand break repair
.
Br. J. Cancer
122
,
613
623
13.
Michelini
F.
,
Jalihal
A.P.
,
Francia
S.
,
Meers
C.
,
Neeb
Z.T.
,
Rossiello
F.
et al.
(
2018
)
From “Cellular” RNA to “Smart” RNA: multiple roles of rna in genome stability and beyond
.
Chem. Rev.
118
,
4365
4403
[PubMed]
14.
Jimeno
S.
,
Prados-Carvajal
R.
and
Huertas
P.
(
2019
)
The role of RNA and RNA-related proteins in the regulation of DNA double strand break repair pathway choice
.
DNA Repair. (Amst.)
81
,
102662
[PubMed]
15.
Gullerova
M.
(
2015
)
Long non-coding RNA
. In
Genomic Elements in Health, Disease and Evolution: Junk DNA
, pp.
83
108
,
Springer-Verlag London Ltd.
16.
Francia
S.
,
Michelini
F.
,
Saxena
A.
,
Tang
D.
,
de Hoon
M.
,
Anelli
V.
et al.
(
2012
)
Site-specific DICER and DROSHA RNA products control the DNA-damage response
.
Nature
488
,
231
235
[PubMed]
17.
Shkreta
L.
and
Chabot
B.
(
2015
)
The RNA splicing response to DNA damage
.
Biomolecules
5
,
4
,
2935
2977
[PubMed]
18.
Wickramasinghe
V.O.
and
Venkitaraman
A.R.
(
2016
)
RNA processing and genome stability: cause and consequence
.
Mol. Cell
61
,
4
,
496
505
[PubMed]
19.
Pong
S.K.
and
Gullerova
M.
(
2018
)
Noncanonical functions of microRNA pathway enzymes - Drosha, DGCR8, Dicer and Ago proteins
.
FEBS Lett.
592
,
2973
2986
[PubMed]
20.
Chowdhury
D.
,
Choi
Y.E.
and
Brault
M.E.
(
2013
)
Charity begins at home: non-coding RNA functions in DNA repair
.
Nat. Rev. Mol. Cell Biol.
14
,
181
189
[PubMed]
21.
Wan
G.
,
Mathur
R.
,
Hu
X.
,
Zhang
X.
and
Lu
X.
(
2011
)
miRNA response to DNA damage
.
Trends Biochem. Sci.
36
,
478
484
[PubMed]
22.
Trabucchi
M.
,
Briata
P.
,
Garcia-Mayoral
M.
,
Haase
A.D.
,
Filipowicz
W.
,
Ramos
A.
et al.
(
2009
)
The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs
.
Nature
459
,
1010
1014
[PubMed]
23.
Zhang
X.
,
Wan
G.
,
Berger
F.G.
,
He
X.
and
Lu
X.
(
2011
)
The ATM kinase induces microRNA biogenesis in the DNA damage response
.
Mol. Cell
41
,
371
383
[PubMed]
24.
Rezaeian
A.-H.
,
Khanbabaei
H.
and
Calin
G.A.
(
2020
)
Therapeutic potential of the miRNA-ATM axis in the management of tumor radioresistance
.
Cancer Res.
80
,
139
150
[PubMed]
25.
Burger
K.
,
Ketley
R.F.
and
Gullerova
M.
(
2019
)
Beyond the Trinity of ATM, ATR, and DNA-PK: multiple kinases shape the DNA damage response in concert with RNA metabolism
.
Front. Mol. Biosci.
6
,
61
26.
Tu
C.C.
,
Zhong
Y.
,
Nguyen
L.
,
Tsai
A.
,
Sridevi
P.
,
Tarn
W.Y.
et al.
(
2015
)
The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage.
Sci Signal
8
,
ra64
[PubMed]
27.
Kawai
S.
and
Amano
A.
(
2012
)
BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex
.
J. Cell Biol.
197
,
201
208
[PubMed]
28.
Sharma
V.
and
Misteli
T.
(
2013
)
Non-coding RNAs in DNA damage and repair
.
FEBS Lett.
587
,
1832
1839
[PubMed]
29.
Hatano
K.
,
Kumar
B.
,
Zhang
Y.
,
Coulter
J.B.
,
Hedayati
M.
,
Mears
B.
et al.
(
2015
)
A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation
.
Nucleic Acids Res.
43
,
4075
4086
[PubMed]
30.
Lal
A.
,
Pan
Y.
,
Navarro
F.
,
Dykxhoorn
D.M.
,
Moreau
L.
,
Meire
E.
et al.
(
2009
)
miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells
.
Nat. Struct. Mol. Biol.
16
,
492
498
[PubMed]
31.
Chen
S.
,
Liu
R.
,
Wang
Q.
,
Qi
Z.
,
Hu
Y.
,
Zhou
P.
et al.
(
2019
)
MiR-34s negatively regulate homologous recombination through targeting RAD51
.
Arch. Biochem. Biophys.
666
,
73
82
[PubMed]
32.
Choi
Y.E.
,
Pan
Y.
,
Park
E.
,
Konstantinopoulos
P.A.
,
De
S.
,
D’Andrea
A.D.
et al.
(
2014
)
MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability
.
Elife
3
,
e02445
33.
Wang
Y.
,
Huang
J.-W.
,
Li
M.
,
Cavenee
W.K.
,
Mitchell
P.S.
,
Zhou
X.
et al.
(
2011
)
MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression
.
Mol. Cancer Res.
9
,
1100
1111
[PubMed]
34.
Landau
D.-A.
and
Slack
F.J.
(
2011
)
MicroRNAs in mutagenesis, genomic instability, and DNA repair
.
Semin. Oncol.
38
,
743
751
[PubMed]
35.
Hu
H.
,
Du
L.
,
Nagabayashi
G.
,
Seeger
R.C.
and
Gatti
R.A.
(
2010
)
ATM is down-regulated by N-Myc-regulated microRNA-421
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
1506
1511
[PubMed]
36.
Mohiuddin
I.S.
and
Kang
M.H.
(
2019
)
DNA-PK as an emerging therapeutic target in cancer
.
Front. Oncol.
9
,
635
[PubMed]
37.
Yang
L.
,
Yang
B.
,
Wang
Y.
,
Liu
T.
,
He
Z.
,
Zhao
H.
et al.
(
2019
)
The CTIP-mediated repair of TNF-α-induced DNA double-strand break was impaired by miR-130b in cervical cancer cell
.
Cell Biochem. Funct.
37
,
534
544
[PubMed]
38.
Martin
N.T.
,
Nakamura
K.
,
Davies
R.
,
Nahas
S.A.
,
Brown
C.
,
Tunuguntla
R.
et al.
(
2013
)
ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response
.
PLoS Genet.
9
,
e1003505
[PubMed]
39.
Meghani
K.
,
Fuchs
W.
,
Detappe
A.
,
Drané
P.
,
Gogola
E.
,
Rottenberg
S.
et al.
(
2018
)
Multifaceted impact of microRNA 493-5p on genome-stabilizing pathways induces platinum and PARP inhibitor resistance in BRCA2-mutated carcinomas
.
Cell Rep.
23
,
100
111
[PubMed]
40.
Lee
J.-H.
,
Park
S.-J.
,
Jeong
S.-Y.
,
Kim
M.-J.
,
Jun
S.
,
Lee
H.-S.
et al.
2015
MicroRNA-22 suppresses DNA repair and promotes genomic instability through targeting of MDC1
,
Cancer Res.
75
,
7
,
1298
1310
41.
Kofman
A.V.
,
Kim
J.
,
Park
S.Y.
,
Dupart
E.
,
Letson
C.
,
Bao
Y.
et al.
(
2013
)
microRNA-34a promotes DNA damage and mitotic catastrophe
.
Cell Cycle
12
,
3500
3511
[PubMed]
42.
Moskwa
P.
,
Buffa
F.M.
,
Pan
Y.
,
Panchakshari
R.
,
Gottipati
P.
,
Muschel
R.J.
et al.
(
2011
)
miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors
.
Mol. Cell
41
,
210
220
[PubMed]
43.
Mogilyansky
E.
,
Clark
P.
,
Quann
K.
,
Zhou
H.
,
Londin
E.
,
Jing
Y.
et al.
(
2016
)
Post-transcriptional regulation of BRCA2 through interactions with miR-19a and miR-19b
.
Front. Genet.
7
,
143
[PubMed]
44.
Piotto
C.
,
Biscontin
A.
,
Millino
C.
and
Mognato
M.
(
2018
)
Functional validation of miRNAs targeting genes of DNA double-strand break repair to radiosensitize non-small lung cancer cells
.
Biochim. Biophys. Acta Gene Regul. Mech.
1861
,
1102
1118
[PubMed]
45.
Rojas
E.
,
Martinez-Pacheco
M.
,
Rodriguez-Sastre
M.A.
,
Ramos-Espinosa
P.
and
Valverde
M.
(
2020
)
Post-transcriptional regulation of Rad51c by miR-222 contributes cellular transformation
.
PLoS ONE
15
,
e0221681
[PubMed]
46.
Chai
Z.
,
Yin
X.
,
Chen
J.
,
Shi
J.
,
Sun
J.
,
Liu
C.
et al.
(
2019
)
MicroRNA-101 modulates cisplatin chemoresistance in liver cancer cells via the DNA-PKcs signaling pathway
.
Oncol. Lett.
18
,
3655
3663
[PubMed]
47.
Zhang
Z.-Y.
,
Fu
S.-L.
,
Xu
S.-Q.
,
Zhou
X.
,
Liu
X.-S.
,
Xu
Y.-J.
et al.
(
2015
)
By downregulating Ku80, hsa-miR-526b suppresses non-small cell lung cancer
.
Oncotarget
6
,
1462
1477
[PubMed]
48.
Choi
Y.E.
,
Meghani
K.
,
Brault
M.-E.
,
Leclerc
L.
,
He
Y.J.
,
Day
T.A.
et al.
(
2016
)
Platinum and PARP inhibitor resistance due to overexpression of microRNA-622 in BRCA1-mutant ovarian cancer
.
Cell Rep.
14
,
429
439
[PubMed]
49.
Smolinska
A.
,
Swoboda
J.
,
Fendler
W.
,
Lerch
M.M.
,
Sendler
M.
and
Moskwa
P.
(
2020
)
MiR-502 is the first reported miRNA simultaneously targeting two components of the classical non-homologous end joining (C-NHEJ) in pancreatic cell lines
.
Heliyon
6
,
e03187
[PubMed]
50.
Liao
C.
,
Xiao
W.
,
Zhu
N.
,
Liu
Z.
,
Yang
J.
,
Wang
Y.
et al.
(
2015
)
MicroR-545 enhanced radiosensitivity via suppressing Ku70 expression in Lewis lung carcinoma xenograft model
.
Cancer Cell Int.
15
,
56
[PubMed]
51.
Mo
L.-J.
,
Song
M.
,
Huang
Q.-H.
,
Guan
H.
,
Liu
X.-D.
,
Xie
D.-F.
et al.
(
2018
)
Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4
.
Br. J. Cancer
119
,
492
502
[PubMed]
52.
Liu
R.
,
Zhang
Q.
,
Shen
L.
,
Chen
S.
,
He
J.
,
Wang
D.
et al.
(
2020
)
Long noncoding RNA lnc-RI regulates DNA damage repair and radiation sensitivity of CRC cells through NHEJ pathway
.
Cell Biol. Toxicol
53.
Hu
B.
,
Wang
X.
,
Hu
S.
,
Ying
X.
,
Wang
P.
,
Zhang
X.
et al.
(
2017
)
miR-21-mediated radioresistance occurs via promoting repair of DNA double strand breaks
.
J. Biol. Chem.
292
,
3531
3540
[PubMed]
54.
Burger
K.
and
Gullerova
M.
(
2018
)
Nuclear re-localization of Dicer in primary mouse embryonic fibroblast nuclei following DNA damage
.
PLoS Genet.
14
,
e1007151
[PubMed]
55.
Burger
K.
,
Schlackow
M.
,
Potts
M.
,
Hester
S.
,
Mohammed
S.
and
Gullerova
M.
(
2017
)
Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage
.
J. Cell Biol.
216
,
2373
2389
[PubMed]
56.
Much
C.
,
Auchynnikava
T.
,
Pavlinic
D.
,
Buness
A.
,
Rappsilber
J.
,
Benes
V.
et al.
(
2016
)
Endogenous mouse Dicer is an exclusively cytoplasmic protein
.
PLoS Genet.
12
,
6
,
e1006095
[PubMed]
57.
White
E.
,
Schlackow
M.
,
Kamieniarz-Gdula
K.
,
Proudfoot
N.J.
and
Gullerova
M.
(
2014
)
Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA
.
Nat. Struct. Mol. Biol.
21
,
552
559
[PubMed]
58.
Passon
N.
,
Gerometta
A.
,
Puppin
C.
,
Lavarone
E.
,
Puglisi
F.
,
Tell
G.
et al.
(
2012
)
Expression of Dicer and Drosha in triple-negative breast cancer
.
J. Clin. Pathol.
65
,
320
326
[PubMed]
59.
Gagnon
K.T.
,
Li
L.
,
Chu
Y.
,
Janowski
B.A.
and
Corey
D.R.
(
2014
)
RNAi factors are present and active in human cell nuclei
.
Cell Rep.
6
,
1
,
211
221
[PubMed]
60.
Francia
S.
,
Cabrini
M.
,
Matti
V.
,
Oldani
A.
and
d’Adda di Fagagna
F.
(
2016
)
DICER, DROSHA and DNA damage response RNAs are necessary for the secondary recruitment of DNA damage response factors
.
J. Cell Sci.
129
,
1468
1476
[PubMed]
61.
Michelini
F.
,
Pitchiaya
S.
,
Vitelli
V.
,
Sharma
S.
,
Gioia
U.
,
Pessina
F.
et al.
(
2017
)
Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks
.
Nat. Cell Biol.
19
,
1400
1411
[PubMed]
62.
Pessina
F.
,
Giavazzi
F.
,
Yin
Y.
,
Gioia
U.
,
Vitelli
V.
,
Galbiati
A.
et al.
(
2019
)
Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors
.
Nat. Cell Biol.
21
,
1286
1299
[PubMed]
63.
Burger
K.
,
Schlackow
M.
and
Gullerova
M.
(
2019
)
Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks
.
Nucleic Acids Res.
47
,
7
,
3467
3484
64.
Bonath
F.
,
Domingo-Prim
J.
,
Tarbier
M.
,
Friedländer
M.R.
and
Visa
N.
(
2018
)
Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks
.
Nucleic Acids Res.
46
,
11869
11882
[PubMed]
65.
Lee
S.
,
Kopp
F.
,
Chang
T.C.
,
Sataluri
A.
,
Chen
B.
,
Sivakumar
S.
et al.
(
2016
)
Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins
.
Cell
164
,
69
80
[PubMed]
66.
Uszczynska-Ratajczak
B.
,
Lagarde
J.
,
Frankish
A.
,
Guigó
R.
and
Johnson
R.
(
2018
)
Towards a complete map of the human long non-coding RNA transcriptome
.
Nat. Rev. Genet.
19
,
535
548
[PubMed]
67.
Yang
M.
,
Sun
Y.
,
Xiao
C.
,
Ji
K.
,
Zhang
M.
,
He
N.
et al.
(
2019
)
Integrated analysis of the altered lncRNAs and mRNAs expression in 293T cells after ionizing radiation exposure
.
Int. J. Mol. Sci.
20
,
2968
68.
Cuella-Martin
R.
,
Oliveira
C.
,
Lockstone
H.E.
,
Snellenberg
S.
,
Grolmusova
N.
and
Chapman
J.R.
(
2016
)
53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
.
Mol. Cell
64
,
51
64
[PubMed]
69.
Deng
B.
,
Xu
W.
,
Wang
Z.
,
Liu
C.
,
Lin
P.
,
Li
B.
et al.
(
2019
)
An LTR retrotransposon-derived lncRNA interacts with RNF169 to promote homologous recombination
.
EMBO Rep.
20
,
e47650
[PubMed]
70.
Typas
D.
and
Mailand
N.
(
2019
)
An unorthodox partnership in DNA repair pathway choice
.
EMBO Rep.
20
,
e49105
[PubMed]
71.
Poulsen
M.
,
Lukas
C.
,
Lukas
J.
,
Bekker-Jensen
S.
and
Mailand
N.
(
2012
)
Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks
.
J. Cell Biol.
197
,
189
199
[PubMed]
72.
Zhao
K.
,
Wang
X.
,
Xue
X.
,
Li
L.
and
Hu
Y.
(
2020
)
A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers
.
PLoS Biol.
18
,
e3000666
[PubMed]
73.
Munschauer
M.
,
Nguyen
C.T.
,
Sirokman
K.
,
Hartigan
C.R.
,
Hogstrom
L.
,
Engreitz
J.M.
et al.
(
2018
)
The NORAD lncRNA assembles a topoisomerase complex critical for genome stability
.
Nature
561
,
132
136
74.
Tichon
A.
,
Gil
N.
,
Lubelsky
Y.
,
Havkin Solomon
T.
,
Lemze
D.
,
Itzkovitz
S.
et al.
(
2016
)
A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells
.
Nat. Commun.
7
,
12209
[PubMed]
75.
Elguindy
M.M.
,
Kopp
F.
,
Goodarzi
M.
,
Rehfeld
F.
,
Thomas
A.
,
Chang
T.-C.
et al.
(
2019
)
PUMILIO, but not RBMX, binding is required for regulation of genomic stability by noncoding RNA NORAD
.
Elife
8
,
e48625
76.
Tichon
A.
,
Perry
R.B.T.
,
Stojic
L.
and
Ulitsky
I.
(
2018
)
SAM68 is required for regulation of pumilio by the NORAD long noncoding RNA
.
Genes Dev.
32
,
70
78
[PubMed]
77.
Yang
Z.
,
Zhao
Y.
,
Lin
G.
,
Zhou
X.
,
Jiang
X.
and
Zhao
H.
(
2019
)
Noncoding RNA activated by DNA damage (NORAD): Biologic function and mechanisms in human cancers.
Clin. Chim. Acta
489
,
5
9
[PubMed]
78.
Wan
G.
,
Mathur
R.
,
Hu
X.
,
Liu
Y.
,
Zhang
X.
,
Peng
G.
et al.
(
2013
)
Long non-coding RNA ANRIL (CDKN2B-AS) is induced by the ATM-E2F1 signaling pathway
.
Cell. Signal.
25
,
1086
1095
[PubMed]
79.
Hung
T.
,
Wang
Y.
,
Lin
M.F.
,
Koegel
A.K.
,
Kotake
Y.
,
Grant
G.D.
et al.
(
2011
)
Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters
.
Nat. Genet.
43
,
621
629
[PubMed]
80.
Hu
W.L.
,
Jin
L.
,
Xu
A.
,
Wang
Y.F.
,
Thorne
R.F.
,
Zhang
X.D.
et al.
(
2018
)
GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability
.
Nat. Cell Biol.
20
,
492
502
[PubMed]
81.
Hu
X.
,
Ding
D.
,
Zhang
J.
and
Cui
J.
(
2019
)
Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218
.
Biosci. Rep.
39
,
4
,
BSR20181038
82.
Jiao
Y.
,
Liu
C.
,
Cui
F.-M.
,
Xu
J.-Y.
,
Tong
J.
,
Qi
X.-F.
et al.
(
2015
)
Long intergenic non-coding RNA induced by X-ray irradiation regulates DNA damage response signaling in the human bronchial epithelial BEAS-2B cell line
.
Oncol. Lett.
9
,
169
176
[PubMed]
83.
Hu
Y.
,
Lin
J.
,
Fang
H.
,
Fang
J.
,
Li
C.
,
Chen
W.
et al.
(
2018
)
Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma
.
Leukemia
32
,
2250
2262
[PubMed]
84.
Porro
A.
,
Feuerhahn
S.
,
Delafontaine
J.
,
Riethman
H.
,
Rougemont
J.
and
Lingner
J.
(
2014
)
Functional characterization of the TERRA transcriptome at damaged telomeres
.
Nat. Commun.
5
,
5379
[PubMed]
85.
Webb
C.J.
,
Wu
Y.
and
Zakian
V.A.
(
2013
)
DNA repair at telomeres: keeping the ends intact
.
Cold Spring Harb. Perspect. Biol.
5
,
6
,
a012666
[PubMed]
86.
Schmitt
A.M.
,
Garcia
J.T.
,
Hung
T.
,
Flynn
R.A.
,
Shen
Y.
,
Qu
K.
et al.
(
2016
)
An inducible long noncoding RNA amplifies DNA damage signaling
.
Nat. Genet.
48
,
1370
1376
[PubMed]
87.
Huarte
M.
,
Guttman
M.
,
Feldser
D.
,
Garber
M.
,
Koziol
M.J.
,
Kenzelmann-Broz
D.
et al.
(
2010
)
A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response
.
Cell
142
,
409
419
[PubMed]
88.
Wang
G.
,
Li
Z.
,
Zhao
Q.
,
Zhu
Y.
,
Zhao
C.
,
Li
X.
et al.
(
2014
)
LincRNA-p21 enhances the sensitivity of radiotherapy for human colorectal cancer by targeting the Wnt/β-catenin signaling pathway
.
Oncol. Rep.
31
,
1839
1845
[PubMed]
89.
Prensner
J.R.
,
Chen
W.
,
Iyer
M.K.
,
Cao
Q.
,
Ma
T.
,
Han
S.
et al.
(
2014
)
PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer
.
Cancer Res.
74
,
1651
1660
[PubMed]
90.
Xiong
T.
,
Li
J.
,
Chen
F.
and
Zhang
F.
(
2019
)
PCAT-1: a novel oncogenic long non-coding RNA in human cancers
.
Int. J. Biol. Sci.
15
,
847
856
[PubMed]
91.
Zhang
Y.
,
He
Q.
,
Hu
Z.
,
Feng
Y.
,
Fan
L.
,
Tang
Z.
et al.
(
2016
)
Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer
.
Nat. Struct. Mol. Biol.
23
,
522
530
[PubMed]
92.
Wang
X.
,
Liu
H.
,
Shi
L.
,
Yu
X.
,
Gu
Y.
and
Sun
X.
(
2018
)
LINP1 facilitates DNA damage repair through non-homologous end joining (NHEJ) pathway and subsequently decreases the sensitivity of cervical cancer cells to ionizing radiation
.
Cell Cycle
17
,
4
,
439
447
93.
Sharma
V.
,
Khurana
S.
,
Kubben
N.
,
Abdelmohsen
K.
,
Oberdoerffer
P.
,
Gorospe
M.
et al.
(
2015
)
A BRCA1‐interacting lncRNA regulates homologous recombination
.
EMBO Rep.
16
,
11
,
1520
1534
[PubMed]
94.
Gazy
I.
,
Zeevi
D.A.
,
Renbaum
P.
,
Zeligson
S.
,
Eini
L.
,
Bashari
D.
et al.
(
2015
)
TODRA, a lncRNA at the RAD51 locus, is oppositely regulated to RAD51, and enhances RAD51-dependent DSB (double strand break) repair
.
PLoS ONE
10
,
e0134120
[PubMed]
95.
Shen
L.
,
Wang
Q.
,
Liu
R.
,
Chen
Z.
,
Zhang
X.
,
Zhou
P.
et al.
(
2018
)
LncRNA lnc-RI regulates homologous recombination repair of DNA double-strand breaks by stabilizing RAD51 mRNA as a competitive endogenous RNA
.
Nucleic Acids Res.
46
,
717
729
[PubMed]
96.
Betts
J.A.
,
Moradi Marjaneh
M.
,
Al-Ejeh
F.
,
Lim
Y.C.
,
Shi
W.
,
Sivakumaran
H.
et al.
(
2017
)
Long noncoding RNAs CUPID1 and CUPID2 mediate breast cancer risk at 11q13 by modulating the response to DNA damage
.
Am. J. Hum. Genet.
101
,
255
266
[PubMed]
97.
Hu
Z.
,
Mi
S.
,
Zhao
T.
,
Peng
C.
,
Peng
Y.
,
Chen
L.
et al.
(
2020
)
BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites
.
EMBO J.
39
e104133
[PubMed]
98.
Hegazy
Y.A.
,
Fernando
C.M.
and
Tran
E.J.
(
2020
)
The balancing act of R-loop biology: the good, the bad, and the ugly
.
J. Biol. Chem.
295
,
905
913
[PubMed]
99.
Skourti-Stathaki
K.
and
Proudfoot
N.J.
(
2014
)
A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression
.
Genes Dev.
28
,
13
,
1384
1396
100.
Cohen
S.
,
Puget
N.
,
Lin
Y.-L.
,
Clouaire
T.
,
Aguirrebengoa
M.
,
Rocher
V.
et al.
(
2018
)
Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations
.
Nat. Commun.
9
,
533
[PubMed]
101.
Niehrs
C.
and
Luke
B.
(
2020
)
Regulatory R-loops as facilitators of gene expression and genome stability
.
Nat. Rev. Mol. Cell Biol.
21
,
167
178
[PubMed]
102.
Ohle
C.
,
Tesorero
R.
,
Schermann
G.
,
Dobrev
N.
,
Sinning
I.
and
Fischer
T.
(
2016
)
Transient RNA-DNA hybrids are required for efficient double-strand break repair
.
Cell
167
,
4
,
1001
1013
[PubMed]
103.
D'Alessandro
G.
,
Whelan
D.R.
,
Howard
S.M.
,
Vitelli
V.
,
Renaudin
X.
,
Adamowicz
M.
et al.
(
2018
)
BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment
.
Nat. Commun.
9
,
5376
[PubMed]
104.
Britton
S.
,
Dernoncourt
E.
,
Delteil
C.
,
Froment
C.
,
Schiltz
O.
,
Salles
B.
et al.
(
2014
)
DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal
.
Nucleic Acids Res.
42
,
9047
9062
[PubMed]
105.
Yasuhara
T.
,
Kato
R.
,
Hagiwara
Y.
,
Shiotani
B.
,
Yamauchi
M.
,
Nakada
S.
et al.
(
2018
)
Human Rad52 promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair
.
Cell
175
,
558.e11
570.e11
106.
Lu
W.-T.
,
Hawley
B.R.
,
Skalka
G.L.
,
Baldock
R.A.
,
Smith
E.M.
,
Bader
A.S.
et al.
(
2018
)
Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair
.
Nat. Commun.
9
,
532
[PubMed]
107.
Domingo‐Prim
J.
,
Bonath
F.
and
Visa
N.
(
2020
)
RNA at DNA double‐strand breaks: the challenge of dealing with DNA:RNA hybrids
.
Bioessays
42
,
5
1900225
108.
Bader
A.S.
and
Bushell
M.
(
2020
)
DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci
.
Cell Death Dis.
11
,
280
[PubMed]
109.
Jang
Y.
,
Elsayed
Z.
,
Eki
R.
,
He
S.
,
Du
K.-P.
,
Abbas
T.
et al.
(
2020
)
Intrinsically disordered protein RBM14 plays a role in generation of RNA:DNA hybrids at double-strand break sites
.
Proc. Natl. Acad. Sci. U.S.A.
117
,
5329
5338
[PubMed]
110.
Domingo-Prim
J.
,
Endara-Coll
M.
,
Bonath
F.
,
Jimeno
S.
,
Prados-Carvajal
R.
,
Friedländer
M.R.
et al.
(
2019
)
EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
.
Nat. Commun.
10
,
2135
[PubMed]
111.
Alfano
L.
,
Caporaso
A.
,
Altieri
A.
,
Dell’Aquila
M.
,
Landi
C.
,
Bini
L.
et al.
(
2019
)
Depletion of the RNA binding protein HNRNPD impairs homologous recombination by inhibiting DNA-end resection and inducing R-loop accumulation
.
Nucleic Acids Res.
47
,
4068
4085
[PubMed]
112.
Costantino
L.
and
Koshland
D.
(
2018
)
Genome-wide map of R-Loop-induced damage reveals how a subset of R-loops contributes to genomic instability
.
Mol. Cell
71
,
487.e3
497.e3
113.
Nair
L.
,
Chung
H.
and
Basu
U.
(
2020
)
Regulation of long non-coding RNAs and genome dynamics by the RNA surveillance machinery
.
Nat. Rev. Mol. Cell Biol.
21
,
123
136
[PubMed]
114.
Thapar
R.
,
Bacolla
A.
,
Oyeniran
C.
,
Brickner
J.
,
Chinnam
N.B.
,
Mosammaparast
N.
et al.
(
2018
)
RNA modifications: reversal mechanisms and cancer
.
Biochemistry
58
,
5
,
312
329
[PubMed]
115.
Haruehanroengra
P.
,
Zheng
Y.Y.
,
Zhou
Y.
,
Huang
Y.
and
Sheng
J.
(
2020
)
RNA modifications and cancer
.
RNA Biol.
[PubMed]
116.
Zhang
J.
(
2017
)
Brothers in arms: emerging roles of RNA epigenetics in DNA damage repair
.
Cell Biosci.
7
,
24
117.
Zhou
K.I.
,
Shi
H.
,
Lyu
R.
,
Wylder
A.C.
,
Matuszek
Ż
,
Pan
J.N.
et al.
(
2019
)
Regulation of co-transcriptional pre-mRNA splicing by m6A through the low-complexity protein hnRNPG
.
Mol. Cell
76
,
70.e9
81.e9
118.
Yang
Y.
,
Hsu
P.J.
,
Chen
Y.-S.
and
Yang
Y.-G.
(
2018
)
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism
.
Cell Res.
28
,
616
624
[PubMed]
119.
Mao
Y.
,
Dong
L.
,
Liu
X.-M.
,
Guo
J.
,
Ma
H.
,
Shen
B.
et al.
(
2019
)
m6A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2
.
Nat. Commun.
10
,
5332
[PubMed]
120.
Wang
X.
,
Zhao
B.S.
,
Roundtree
I.A.
,
Lu
Z.
,
Han
D.
,
Ma
H.
et al.
(
2015
)
N(6)-methyladenosine modulates messenger RNA translation efficiency
.
Cell
161
,
1388
1399
[PubMed]
121.
Coots
R.A.
,
Liu
X.-M.
,
Mao
Y.
,
Dong
L.
,
Zhou
J.
,
Wan
J.
et al.
(
2017
)
m6A facilitates eIF4F-independent mRNA translation
.
Mol. Cell
68
,
504.e7
514.e7
122.
Hirayama
M.
,
Wei
F.-Y.
,
Chujo
T.
,
Oki
S.
,
Yakita
M.
,
Kobayashi
D.
et al.
(
2020
)
FTO demethylates Cyclin D1 mRNA and controls cell-cycle progression
.
Cell Rep.
31
,
107464
[PubMed]
123.
Fei
Q.
,
Zou
Z.
,
Roundtree
I.A.
,
Sun
H.-L.
and
He
C.
(
2020
)
YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators
.
PLoS Biol.
18
,
e3000664
[PubMed]
124.
Meyer
K.D.
and
Jaffrey
S.R.
(
2014
)
The dynamic epitranscriptome: N6-methyladenosine and gene expression control
.
Nat. Rev. Mol. Cell Biol.
15
,
313
326
[PubMed]
125.
Yang
X.
,
Liu
M.
,
Li
M.
,
Zhang
S.
,
Hiju
H.
,
Sun
J.
et al.
(
2020
)
Epigenetic modulations of noncoding RNA: a novel dimension of cancer biology
.
Mol. Cancer
19
,
64
[PubMed]
126.
Zaccara
S.
,
Ries
R.J.
and
Jaffrey
S.R.
(
2019
)
Reading, writing and erasing mRNA methylation
.
Nat. Rev. Mol. Cell Biol.
20
,
608
624
[PubMed]
127.
Yoneda
R.
,
Ueda
N.
,
Uranishi
K.
,
Hirasaki
M.
and
Kurokawa
R.
(
2020
)
Long noncoding RNA pncRNA-D reduces cyclin D1 gene expression and arrests cell cycle through RNA m6A modification
.
J. Biol. Chem.
295
,
5626
5639
[PubMed]
128.
Ban
Y.
,
Tan
P.
,
Cai
J.
,
Li
J.
,
Hu
M.
,
Zhou
Y.
et al.
(
2020
)
LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma
.
Mol. Oncol.
14
,
6
,
1282
1296
[PubMed]
129.
Guan
K.
,
Liu
X.
,
Li
J.
,
Ding
Y.
,
Li
J.
,
Cui
G.
et al.
(
2020
)
Expression status and prognostic value Of M6A-associated genes in gastric cancer
.
J. Cancer
11
,
3027
3040
[PubMed]
130.
Barbieri
I.
,
Tzelepis
K.
,
Pandolfini
L.
,
Shi
J.
,
Millán-Zambrano
G.
,
Robson
S.C.
et al.
(
2017
)
Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
.
Nature
552
,
126
131
[PubMed]
131.
Zhou
J.
,
Wan
J.
,
Gao
X.
,
Zhang
X.
,
Jaffrey
S.R.
and
Qian
S.-B.
(
2015
)
Dynamic m 6 A mRNA methylation directs translational control of heat shock response
.
Nature
526
,
591
594
[PubMed]
132.
Zhang
Q.
,
Riddle
R.C.
,
Yang
Q.
,
Rosen
C.R.
,
Guttridge
D.C.
,
Dirckx
N.
et al.
(
2019
)
The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage
.
Proc. Natl. Acad. Sci. U.S.A.
116
,
17980
17989
[PubMed]
133.
Xiang
Y.
,
Laurent
B.
,
Hsu
C.H.
,
Nachtergaele
S.
,
Lu
Z.
,
Sheng
W.
et al.
(
2017
)
RNA m6 A methylation regulates the ultraviolet-induced DNA damage response
.
Nature
543
,
573
576
[PubMed]
134.
Svobodová Kovaříková
A.
,
Stixová
L.
,
Kovařík
A.
,
Komůrková
D.
,
Legartová
S.
,
Fagherazzi
P.
et al.
(
2020
)
N6-adenosine methylation in RNA and a reduced M3G/TMG level in non-coding RNAs appear at microirradiation-induced DNA lesions
.
Cells
9
,
360
135.
Visvanathan
A.
,
Patil
V.
,
Arora
A.
,
Hegde
A.S.
,
Arivazhagan
A.
,
Santosh
V.
et al.
(
2018
)
Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance
.
Oncogene
37
,
522
533
[PubMed]
136.
Abakir
A.
,
Giles
T.C.
,
Cristini
A.
,
Foster
J.M.
,
Dai
N.
,
Starczak
M.
et al.
(
2020
)
N 6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells
.
Nat. Genet.
52
,
48
55
[PubMed]
137.
Yang
X.
,
Liu
Q.L.
,
Xu
W.
,
Zhang
Y.C.
,
Yang
Y.
,
Ju
L.F.
et al.
(
2019
)
m6A promotes R-loop formation to facilitate transcription termination
.
Cell Res.
29
,
1035
1038
138.
Marnef
A.
and
Legube
G.
(
2020
)
m6A RNA modification as a new player in R-loop regulation
.
Nat. Genet.
57
,
27
28
[PubMed]
139.
Li
X.
,
Xiong
X.
,
Zhang
M.
,
Wang
K.
,
Chen
Y.
,
Zhou
J.
et al.
(
2017
)
Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts
.
Mol. Cell
68
,
5
,
993
1005
140.
Li
X.
,
Xiong
X.
,
Wang
K.
,
Wang
L.
,
Shu
X.
,
Ma
S.
et al.
(
2016
)
Transcriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome
.
Nat. Chem. Biol.
12
,
311
316
141.
Zhang
C.
and
Jia
G.
(
2018
)
Reversible RNA Modification N1-methyladenosine (m1A) in mRNA and tRNA
.
Genomics Proteomics Bioinformatics
16
,
155
161
142.
Safra
M.
,
Sas-Chen
A.
,
Nir
R.
,
Winkler
R.
,
Nachshon
A.
,
Bar-Yaacov
D.
et al.
(
2017
)
The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution
.
Nature
551
,
251
255
[PubMed]
143.
Grozhik
A.V.
,
Olarerin-George
A.O.
,
Sindelar
M.
,
Li
X.
,
Gross
S.S.
and
Jaffrey
S.R.
(
2019
)
Antibody cross-reactivity accounts for widespread appearance of m1A in 5′UTRs
.
Nat. Commun.
10
,
5126
[PubMed]
144.
Kim
D.-S.
,
Challa
S.
,
Jones
A.
and
Kraus
W.L.
(
2020
)
PARPs and ADP-ribosylation in RNA biology: from RNA expression and processing to protein translation and proteostasis
.
Genes Dev.
34
,
302
320
145.
Munnur
D.
,
Bartlett
E.
,
Mikolčević
P.
,
Kirby
I.T.
,
Matthias Rack
J.G.
,
Mikoč
A.
et al.
(
2019
)
Reversible ADP-ribosylation of RNA
.
Nucleic Acids Res.
47
,
5658
5669
[PubMed]
146.
Zhang
F.
,
Lou
L.
,
Peng
B.
,
Song
X.
,
Reizes
O.
,
Almasan
A.
et al.
(
2020
)
Nudix hydrolase NUDT16 regulates 53BP1 protein by reversing 53BP1 ADP-ribosylation
.
Cancer Res.
80
,
999
1010
[PubMed]
147.
Pears
C.J.
,
Couto
C.-M.
,
Wang
H.-Y.
,
Borer
C.
,
Kiely
R.
and
Lakin
N.D.
(
2012
)
The role of ADP-ribosylation in regulating DNA double-strand break repair
.
Cell Cycle
11
,
48
56
[PubMed]
148.
Motorin
Y.
and
Helm
M.
(
2019
)
Methods for RNA modification mapping using deep sequencing: established and new emerging technologies
.
Genes
10
,
35
[PubMed]
149.
Wein
S.
,
Andrews
B.
,
Sachsenberg
T.
,
Santos-Rosa
H.
,
Kohlbacher
O.
,
Kouzarides
T.
et al.
(
2020
)
A computational platform for high-throughput analysis of RNA sequences and modifications by mass spectrometry
.
Nat. Commun.
11
,
926
[PubMed]
150.
Wang
W.-T.
,
Han
C.
,
Sun
Y.-M.
,
Chen
T.-Q.
and
Chen
Y.-Q.
(
2019
)
Noncoding RNAs in cancer therapy resistance and targeted drug development
.
J. Hematol. Oncol.
12
,
55
[PubMed]
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