PALB2 [partner and localizer of BRCA2 (breast cancer early-onset 1)] has emerged as a key player in the maintenance of genome integrity. Biallelic mutations in PALB2 cause FA (Fanconi's anaemia) subtype FA-N, a devastating inherited disorder marked by developmental abnormalities, bone marrow failure and childhood cancer susceptibility, whereas monoallelic mutations predispose to breast, ovarian and pancreatic cancer. The tumour suppressor role of PALB2 has been intimately linked to its ability to promote HR (homologous recombination)-mediated repair of DNA double-strand breaks. Because PALB2 lies at the crossroads between FA, HR and cancer susceptibility, understanding its function has become the primary focus of several studies. The present review discusses a current synthesis of the contribution of PALB2 to these pathways. We also provide a molecular description of FA- or cancer-associated PALB2 mutations.

INTRODUCTION

Human cells are under constant attack by endogenous or exogenous agents that induce tens of thousands of instances of DNA damage each day [1]. Genome integrity is directly threatened by these lesions, which must be identified and eliminated quickly. Cells have thus developed fine-tuned signalling and repair mechanisms for resolving these harmful injuries and ensuring DNA fidelity. Of all the DNA insults, DNA DSBs (double-strand breaks) and ICLs (interstrand cross-links) are the most toxic and challenging to repair because they affect both strands of DNA. Failure to repair DSBs and ICLs can lead to genome rearrangements and contribute to carcinogenesis.

DSBs can arise from exogenous sources, such as ionizing radiation, radiomimetic drugs and cancer chemotherapeutics, or from endogenous sources including ROS (reactive oxygen species) generated during cellular metabolism, collapsed replication forks, and nucleases during programmed genome rearrangements in lymphocytes and germ cells [2,3]. HR (homologous recombination) is a major pathway for DSB repair, as is NHEJ (non-homologous end-joining). DSB repair by NHEJ takes place throughout the cell cycle via direct rejoining of the two broken extremities, and is potentially mutagenic as it can introduce deletions and insertions. In contrast, HR is active primarily in S/G2-phase, during which it relies on the sequence homology of an intact sister chromatid for faithful DNA repair and is preferred over NHEJ [2,4]. HR also repairs DSBs produced by stalled or collapsed replication forks or created during ICL processing [5,6].

ICLs can be introduced by exogenous agents such as DEB (diepoxybutane), CDDP (cisplatin) and MMC (mitomycin C), but can also be produced endogenously by aldehydes and by-products of different metabolic pathways such as lipid peroxidation [7]. ICLs covalently link both strands of a DNA duplex, thereby blocking replication and ultimately leading to DSB formation in the repair process. Their complexity requires the sequential intervention of several repair enzymes that belong to distinct pathways, including nucleotide excision repair, translesion synthesis and HR [6]. The FA (Fanconi's anaemia) pathway ensures the fine co-ordination of these repair activities [8]. PALB2 [partner and localizer of BRCA2 (breast cancer early-onset 1)] (FANCN) belongs, together with BRCA2 (FANCD1), BRIP1/BACH1 (FANCJ) and RAD51C (FANCO) to a small subset of genes that are key players in both the HR and FA pathways. When mutated, these genes are associated with FA and breast/ovarian cancer, establishing a fascinating linkage between these two pathways and cancer predisposition. In the present review, we provide an overview of the molecular mechanisms that underlie the tumour suppressor function of PALB2. We also discuss the known cancer-associated mutations of PALB2.

PALB2: A KEY PLAYER FOR GENOME STABILITY

HR is important for DSB repair in the late S- and G2-phases of the cell cycle. By using the sister chromatid as a template, HR allows the faithful recovery of genetic information [9]. The mechanism involves 3′-ssDNA tails generated by resection of DSBs [10] that are bound initially by RPA (replication protein A) complexes to protect ssDNA and trigger ATR (ataxia telangiectasia- and Rad3-related)-dependent checkpoint signalling [11]. The RAD51 recombinase is a key player to initiate genetic recombination between sister chromatids in S-phase, to allow the invasion of 3′-ssDNA tails into duplex DNA. RAD51 forms nucleoprotein filaments around the DNA, a structure required for DNA invasion [1214]. In order for the presynaptic filament to assemble, RAD51 must first displace RPA [15]. For this, RAD51 relies on the activity of mediators, such as BRCA2, PALB2 and RAD51 paralogues. Among these, BRCA2 is the best characterized [15].

Brief overview of BRCA2 functions

The BRCA2 gene, localized on the human chromosome 13q12-q13 [16], was identified as a breast cancer susceptibility gene in 1995 [17]. Mutation of this gene has been shown to be responsible for 5–7% of breast cancers, as well as a factor increasing the susceptibility to develop ovarian, prostate or pancreatic cancers. A monoallelic mutation in a patient confers a 50% risk of developing a cancer before the age of 50 and an 80% risk before 70 [18,19]. A biallelic inactivation of BRCA2 leads to FA, a rare genetic disorder caused by a mutation in the genes regulating the repair of DNA ICLs [6]. The human BRCA2 protein is a large protein of 3148 amino acids (384 kDa) essential for HR repair [9,19], as BRCA2-deficient cells harbour a decrease of 80–90% of their HR activity [20]. One of the major roles of BRCA2 is to help to direct the RAD51 recombinase to DSB sites in the nucleus via direct interaction [2124]. It has been shown in BRCA2-deficient cells that RAD51 could no longer localize to DSBs [21,25]. BRCA2 is known to bind ssDNA and dsDNA as well, but with a weaker affinity [26,27]. The DNA-binding domain of BRCA2 is important for the recruitment of RAD51 at DSBs [28,29]. The structure of this domain has been resolved by X-ray crystallography and comprises five domains: an HD (helix domain), three OB (oligonucleotide-binding) domains (OB1, OB2 and OB3) that bind ssDNA, and a Tower domain containing HTH (helix-turn-helix) subdomains, which confers the dsDNA-binding activity [26]. The HD and OB1 domains interact also with the DSS1 protein known to be important for BRCA2 stability [26]. The purification of BRCA2 by the Kowalczykowski, Heyer and West teams led to a better understanding of its role as a mediator of HR repair [3032]. These studies have shown four distinct functions for BRCA2: (i) it stimulates RAD51 filament formation on an ssDNA protected by RPA; (ii) it prevents RAD51 filament formation occuring on dsDNA; (iii) it inhibits the dissociation of RAD51 filaments by preventing ATP hydrolysis; and (iv) it stimulates RAD51 filament activity of strand exchange between homologous sequences [3032].

Contributions of PALB2 to genome maintenance and HR

The FLJ21816/LOC79728 protein was identified in 2006 by Xia et al. [33] as a major BRCA2-interacting protein. It was subsequently named PALB2, for ‘partner and localizer of BRCA2’. The PALB2 gene is located on chromosome 16p12.2 and consists of 13 exons, which encode a protein of 1186 amino acids (131 kDa) [34]. The first level of control by which PALB2 may protect the genome is through reducing the burden of oxidative stress (Figure 1). Indeed, an interesting interactor of PALB2 is KEAP1 (Kelch-like ECH-associated protein 1), a cysteine-rich oxidative stress sensor, establishing PALB2 as a regulator of cellular redox homoeostasis [35]. NRF2 (nuclear factor-erythroid 2-related factor 2) is an important transcription factor activating the expression of a large number of ARE (antioxidant-response element)-containing genes. Under normal conditions, KEAP1 binds to NRF2 and functions as an E3 ubiquitin ligase that targets NRF2 for degradation. Upon oxidative stress, KEAP1 is modified on its cysteine residues, leading to a conformational change that disrupts its binding to NRF2. An extensive domain mapping and bioinformatics analysis identified the KEAP1-binding site on PALB2. Interestingly, PALB2 carries a seven-amino-acid motif (LDEETGE) that is highly conserved across mammalian species. This motif is in part identical to the ETGE motif of NRF2 that binds KEAP1. Hence PALB2 enhances NRF2 function by impeding the KEAP1–NRF2 interaction in the nucleus. Consistent with this, depletion of PALB2 leads to increased ROS levels and down-regulation of a subset of NRF2 target genes. FA cells are generally hypersensitive to oxidative stress; it will therefore be interesting to see whether PALB2 plays an important role in regulating the oxidative stress response in FA cells [35].

Roles of PALB2 in HR

Figure 1
Roles of PALB2 in HR

First, through interaction with KEAP1, PALB2 participates in the protection against DNA damage. The interaction with KEAP1 is also preserved after DNA damage. Secondly, PALB2 interacts with MRG15 which may promote chromatin remodelling. MGR15 is also important for the recruitment of PALB2 after DNA resection. Thirdly, RAD51-mediated D-loop formation is stimulated by the BRCA1–PALB2–BRCA2 complex.

Figure 1
Roles of PALB2 in HR

First, through interaction with KEAP1, PALB2 participates in the protection against DNA damage. The interaction with KEAP1 is also preserved after DNA damage. Secondly, PALB2 interacts with MRG15 which may promote chromatin remodelling. MGR15 is also important for the recruitment of PALB2 after DNA resection. Thirdly, RAD51-mediated D-loop formation is stimulated by the BRCA1–PALB2–BRCA2 complex.

PALB2 is a nuclear protein, associated with chromatin, which favours the subnuclear localization of BRCA2 and RAD51. PALB2 forms ionizing radiation-induced foci that co-localize with BRCA2, γ-H2AX and BRCA1. Importantly, depletion of PALB2 abrogated significantly the efficiency of HR using the I-SceI system [33]. PALB2 deficiency leads to the concomitant loss of BRCA2 and RAD51 localization to DSBs, again highlighting an important function in DSB repair [33]. We have shown that purified PALB2 binds ssDNA and D-loop structures preferentially and interacts directly with RAD51. Similar to BRCA2, PALB2 stimulates RAD51 filament formation on an ssDNA protected by RPA and stimulates ssDNA invasion confirming its function as an HR mediator [36,37] (Figure 1).

The protein domains of PALB2 are very intriguing (Figure 2). First, PALB2 binds BRCA1 through its coiled-coil N-terminal domain [3841]. The coiled-coil domain also promotes PALB2 dimerization [41]. The importance of this domain is illustrated by the observation that its absence increases cell sensitivity to DNA-damaging agents in a manner similar to PALB2 deficiency. The formation of the BRCA1–PALB2 complex, through the coiled-coil domain, is thus essential for recruitment and filament formation by RAD51 at DNA DSBs [40,42]. The coiled-coil domain is also required for the self-interaction of PALB2. Our data suggest a model where, in the absence of DNA damage, PALB2 is dimeric and poorly active. After DNA damage, PALB2 dissociates and interacts with BRCA1 to allow PALB2 localization and HR activation [41]. The regulation of PALB2 dimerization after DNA damage to promote BRCA1 interaction is still misunderstood.

Schematic representation of PALB2 mutations in exons or assigned domains of PALB2

Secondly, PALB2 interacts with BRCA2 through a seven-bladed WD40-type region [33,43]. PALB2 truncations leading to loss of the WD40 domain cause a profound deficiency in HR, as the interaction with BRCA2 is lost. Overexpression of the PALB2 WD40 domain leads to blockage of HR induced by both DSBs and nicks, and sensitizes cells to the PARP [poly(ADP-ribose) polymerase] inhibitor AZD2281 (also named olaparib) [44]. The mechanism whereby HR is reduced following expression of PALB2 WD40 might be via competitive disruption of the normal PALB2–BRCA2 interaction. Interestingly, this dominant-negative disruption by PALB2 WD40 expression leads to compensation, revealing a nick-induced mutagenic NHEJ pathway that is detected only when the HR machinery is blocked [44]. Furthermore, the WD40 domain of PALB2 seems to be an important regulatory platform. By using MS to identify proteins that co-purified with His6–FLAG–RAD51C, Park et al. [45] identified BRCA2 and PALB2 as interacting proteins. It was shown that RAD51C binds directly to the WD40 domain of PALB2. The PALB2 missense mutations/variants p.Leu939Trp, p.Thr1030Ile and p.Leu1143Pro, found in breast cancer patients, were analysed for RAD51C binding. Although binding was not disrupted completely, the p.Leu1143Pro mutant exhibited decreased binding to RAD51C and BRCA2, both in vitro and in human cells. We have found recently that the WD40 region also binds Polη (polymerase η), which has consequences for the proper functioning of the later stages of HR [46]. An important function of HR is to find a template for DNA synthesis from the resected ends. BRCA2 and Polη co-localize at stalled or collapsed replication forks after hydroxyurea treatment. Moreover, PALB2 and BRCA2 interact with Polη and are required to sustain the recruitment of Polη at blocked replication forks. PALB2 and BRCA2 stimulate Polη-dependent DNA synthesis on D-loop substrates. Hence PALB2 and BRCA2 play crucial roles in the initiation of recombination-associated DNA synthesis by Polη-mediated DNA repair [46]. However, Polη is not involved in the repair of DSBs that are not associated with DNA replication, suggesting that other polymerases are involved to extend D-loop structures. Further investigation will be necessary to know whether PALB2 and BRCA2 are also able to regulate the activity of other DNA polymerases.

Thirdly, Bleuyard et al. [47] identified a ChAM (chromatin-association motif) in PALB2 that mediates its chromatin association in both unperturbed and damaged cells. This domain represents an evolutionarily conserved motif in PALB2. Cellular fractionation following expression of a GFP–ChAM fusion construct in HEK (human embryonic kidney)-293T cells revealed that ChAM is bound extensively to chromatin. PALB2 and PALB2ΔChAM bound DNA in a similar manner, suggesting that ChAM mediates chromatin association independently from PALB2 DNA-binding activity. Interestingly, ChAM deletion decreased PALB2 and RAD51 accumulation at DSB sites and led to hypersensitivity to MMC, highlighting the importance of this region in PALB2 regulation.

Siaud et al. [28] investigated the structure and function of the multiple and complex domains of BRCA2. To do this, they created chimaeric BRCA2 peptides, termed mini-BRCA2s. They found that mutations that disrupt DNA binding in the BRCA2 DNA-binding domain significantly reduce or abolish HR when PALB2 binding is absent. However, deletion of the entire DNA-binding domain has little impact on HR when PALB2 binding is present, suggesting that PALB2 can deliver BRCA2 to chromatin, and confirming that the PALB2 interaction domain is essential to deliver BRCA2 to DSBs.

MRG15: another key interactor of PALB2

A new partner called MRG15 has been identified for PALB2 using immunoprecipitation followed by MS analysis [48,49]. MRG15 interacts with the middle part of PALB2 (amino acids 611–764) and seems to be important for PALB2 localization at DSBs. The MRG15 protein is a member of the HAT (histone acetyltransferase) complex Tip60 [50], but also a subunit of the HDAC (histone deacetylase) complex SIN3b/Rpd3s [51,52]. The MRG15 protein has an N-terminal chromodomain (chromatin organization modifier) usually found in proteins associated with chromatin modifications and remodelling, which specifically binds the di- or tri-methylated Lys36 of histone H3 [53]. MRG15 has a well-established role in transcriptional regulation [54,55], but several studies suggest it also has a role in DSB repair. First, MRG15-deficient mouse embryonic fibroblasts are more sensitive to irradiation than wild-type cells, and γ-H2AX and 53BP1 foci formation is delayed [56]. It has been suggested that MRG15, through its MRG domain, interacts with H2B ubiquitylated on Lys123, an epigenetic mark found at DSB sites and important for chromatin relaxation and recruitment of DNA repair proteins [5760]. MRG15 also regulates the acetylation of histone H4 (H4K16), which is essential for DSB signalling and repair by activating ATM [60,61]. Finally, a decrease of approximately 50–60% in HR in MRG15-deficient cells is observed [48]. Taken together, these observations suggest an early role for MRG15 in DSB signalling. However, the interaction with PALB2 implies a later and more direct role in DNA repair. The exact function of MRG15 in this step still needs to be investigated.

These seminal discoveries set the scene for further exploration of whether PALB2, similar to BRCA2, is mutated in other diseases and contributes to tumour suppression.

PALB2 is an FA gene

Shortly after its discovery, PALB2 was found to be biallelically mutated in eight undesignated cases of FA with a family history of breast cancer and in one additional case study by Xia et al. [62]. All patients developed early childhood malignancies with clinical features reminiscent of the FANCD1 group explained by BRCA2 mutations. At the cellular level, phenotypes of PALB2 deficiency included a lack of chromatin-bound BRCA2 and, similar to BRCA2 deficiency, spontaneous chromosome breakage, hypersensitivity to cross-linking agents and impaired formation of RAD51 foci. From these studies, PALB2 has been known as the gene underlying the N-subtype of FA. In 2013, Serra et al. [63] identified a new patient harbouring a PALB2/FANCN mutation and showing a severe phenotype of FA. Interestingly, FANCN was linked to FA-N when biallelically mutated, and to breast/ovarian cancer when monoallelically mutated, linking the FA and HR pathways to breast/ovarian cancer susceptibility. This was one of the key observations suggesting that PALB2 could function in later stages of HR in the ICL repair pathway.

PALB2: AN IMPORTANT TUMOUR SUPPRESSOR

Mutations in BRCA1 and BRCA2 represent a well-established cause of human familial breast and ovarian cancer. However, they account for only 20–30% of all familial breast cancer cases. Given its crucial roles in HR and the FA pathways, the BRCA2-interacting partner PALB2 has recently become a valuable candidate in genetic screening and so emerged as a cancer susceptibility gene worldwide. To date, mutations in PALB2 have been associated with FA, following biallelic mutation [62,64], and with several cancers, including familial breast [65], pancreatic [66] and ovarian cancer [67], with monoallelic mutations. Nowadays, population-based studies have established that PALB2 mutations, albeit rare, are predominantly associated with familial cancer, with some of them conveying substantially higher breast cancer risks that are comparable with those reported for BRCA2 mutations [65,6871]. In the last section of the present review, we describe the mutations of PALB2 found in various cancers.

Mutations of PALB2 in female and male breast cancer

Numerous truncating mutations of PALB2 (we estimate 48 on a protein scale and 49 on a DNA scale) have been found in breast cancer cases without BRCA2 or BRCA1 mutations (Figure 2 and Table 1). Their frequency seems higher, at between 0.6% [67] and 4.8% [72], in patients with a strong history of familial breast cancer when studies were carried out on various populations (British, French Canadian, Finnish, Spanish, Chinese, Italian, Polish, Australian, German, Russian, Ashkenazi Jewish, Northern European, Caucasian and Danish). When studies looked at unselected cases, the frequency decreased to between 0.4% [73] and 2% [74]. Most studies now agree that mutations in PALB2 occur with low frequency in familial breast cancer, with a higher incidence within defined subpopulations.

Table 1
PALB2 truncating mutations found in cancer and Fanconi's anaemia patients

Mutations that alter the splicing are indicated in italics. Mutations that are also found in male breast cancer are indicated in bold.

DNA Protein Reference(s) 
Breast cancer   
 c.48+1G>C  [105
 c.172_175delTTGT p.Gln60Argfs*7 [76,91,105,106
 c.196C>T p.Gln66* [76,92a
 c.229delT p.Cys77Valfs*100 [71
 c.503C>A p.Ser168* [105
 c.509_510delGA p.Arg170Ilefs*14 [67,76,81,84,107
 c.696insT p.Val233Cysfs*2 [106
 c.697delG p.Val233Leufs*5 [74
 c.751C>T p.Gln251* [68,89
 c.757_758delCT p.Leu253Ilefs*3 [76
 c.758insT p.Ser254Ilefs*3 [85,86,108
 c.1027C>T p.Gln343* [109
 c.1037_1041delAAGAA p.Lys346Thr*13 [89
 c.1050_1051delAAinsTCT p.Gln350Hisfs*11 [68,89
 c.1050delAACA p.Thr351Argfs*4 [89
 c.1056_1057delGA p.Lys353Ilefs*7 [69
 c.1240C>T p.Arg414* [76,84,105
 c.1317delG p.Phe440Leufs*12 [78
 c.1479delC p.Thr494Leufs*67 [86
 c.1546delA p.Arg516Glufs*45 [107
 c.1592delT p.Leu531Cysfs*30 [70,71,111
 c.1633G>T p.Glu545* [84,107
 c.1653T>A p.Tyr551* [76
 c.1786G>T p.Gly596* [107
 c.1924delA p.Asp642Cysfs*18 [107
 c.1947_1948insA p.Glu650Argfs*13 [87
 c.1972G>T p.Glu658* [106
 c.2145_2146delTA p.Asp715Glufs*2 [105
 c.2257C>T p.Arg753* [105,112
 c.2323C>T p.Gln775* [79,90
 c.2325insA p.Phe776Ilefs*26 [106
 c.2386G>T p.Gly796* [65,76,106,107
 c.2390delA p.Gln797Hisfs*54 [85
 c.2559C>T p.Gly853fs*21 [76
 c.2606delC p.Val870* [89
 c.2650G>T p.Glu884* [107
 c.2686insT p.Ser896Phefs*32 [76
 c.2718G>A p.Trp906* [76
 c.2761C>T p.Gln921* [84
 c.2835−1G>C  [76,77
 c.2962C>T p.Gln988* [105
 c.2982insT p.Ala995Cysfs*16 [65
 c.3026delCT p.Phe1009Argfs*9 [76
 c.3048delT p.Phe1016Leufs*17 [86
 c.3113G>A p.Trp1038* and two altered spliced forms (p.Gly1028fs*2 and p.9991038del) [65,69,73,76,77,92a,107
 c.3113+5G>C r.28353113del279/p.Ala946fs [107
 c.3116delA p.Asn1039Ilefs*2 [65,69
 c.3202+1G>C  [77
 c.3362delG p.Gly1121Valfs*3 [106
 c.3549C>G p.Tyr1183* [65,69,77,82,107
Breast cancer cases in families with pancreatic cancer   
 c.72delG p.Arg26Glufs*7 [72
 c.1027C>T p.Gln343* [72
 c.1314delA p.Phe440Leufs*12 [72
 c.2920_2921delAA p.Lys974Glufs*5 [72
 c.2962C>T p.Gln988* [96
 c.3497delG p.Gly1166fs [72
 c.3549C>G p.Tyr1183* [96
Pancreatic cancer   
 c.172_175delTTGT p.Gln60Argfs*7 [66
 c.508_509delAG p.Arg170Ilefs*14 [95
 c.1240C>T p.Arg414* [95
 c.1314delA p.Phe440Leufs*12 [96
 c.2515−1G>T  [66
 c.3116delA p.Asn1039Ilefs*2 [66
 c.3201_3561del p.Met1067Ser1186del [94,110
 c.3256C>T p.Arg1086* [66
Ovarian cancer   
 c.172_175delTTGT p.Gln60Argfs*7 [76,91
 c.509_510delGA p.Arg170Ilefs*14 [67
 c.757_758delCT p.Leu253Ilefs*3 [88
 c.758insT p.Ser254Ilefs*3 [92
 c.1050delAACA p.Thr351Argfs*4 [88
 c.1240C>T p.Arg414* [92
 c.1479delC p.Thr494Leufs*67 [92
 c.2167delAT p.Met723Valfs*21 [92
 c.2323C>T p.Gln775* [77
Prostate cancer   
 c.1592delT p.Leu531Cysfs*30 [83
Fanconi's anaemia   
 c.395delT p.Val132Alafs*45 [64
 c.757–758delCT p.Leu253Ilefs*3 [64
 c.1653T>A p.Tyr551* [62
 c.1676–1677delAAinsG p.Gln559Argfs*2 [63
 c.2257C>T p.Arg753* [64
 c.2393_2394insCT p.Thr799Leufs*53 [64
 c.2521delA p.Thr841Glnfs*10 [64
 c.2962C>T p.Gln988* [64
 c.3113+5G>C r.28353113del279/p.Ala946fs [64
 c.3116delA p.Asn1039Ilefs*2 [64
 c.3294_3298delGACGA p.Lys1098Asnfs*23 [64
 c.3323delA p.Tyr1108Serfs*16 [64
 c.3350+4A>G r.3350insGCAG/p.Phe118fs [64
 c.3549C>G p.Tyr1183* [64
 c.3549C>A p.Tyr1183* [64
DNA Protein Reference(s) 
Breast cancer   
 c.48+1G>C  [105
 c.172_175delTTGT p.Gln60Argfs*7 [76,91,105,106
 c.196C>T p.Gln66* [76,92a
 c.229delT p.Cys77Valfs*100 [71
 c.503C>A p.Ser168* [105
 c.509_510delGA p.Arg170Ilefs*14 [67,76,81,84,107
 c.696insT p.Val233Cysfs*2 [106
 c.697delG p.Val233Leufs*5 [74
 c.751C>T p.Gln251* [68,89
 c.757_758delCT p.Leu253Ilefs*3 [76
 c.758insT p.Ser254Ilefs*3 [85,86,108
 c.1027C>T p.Gln343* [109
 c.1037_1041delAAGAA p.Lys346Thr*13 [89
 c.1050_1051delAAinsTCT p.Gln350Hisfs*11 [68,89
 c.1050delAACA p.Thr351Argfs*4 [89
 c.1056_1057delGA p.Lys353Ilefs*7 [69
 c.1240C>T p.Arg414* [76,84,105
 c.1317delG p.Phe440Leufs*12 [78
 c.1479delC p.Thr494Leufs*67 [86
 c.1546delA p.Arg516Glufs*45 [107
 c.1592delT p.Leu531Cysfs*30 [70,71,111
 c.1633G>T p.Glu545* [84,107
 c.1653T>A p.Tyr551* [76
 c.1786G>T p.Gly596* [107
 c.1924delA p.Asp642Cysfs*18 [107
 c.1947_1948insA p.Glu650Argfs*13 [87
 c.1972G>T p.Glu658* [106
 c.2145_2146delTA p.Asp715Glufs*2 [105
 c.2257C>T p.Arg753* [105,112
 c.2323C>T p.Gln775* [79,90
 c.2325insA p.Phe776Ilefs*26 [106
 c.2386G>T p.Gly796* [65,76,106,107
 c.2390delA p.Gln797Hisfs*54 [85
 c.2559C>T p.Gly853fs*21 [76
 c.2606delC p.Val870* [89
 c.2650G>T p.Glu884* [107
 c.2686insT p.Ser896Phefs*32 [76
 c.2718G>A p.Trp906* [76
 c.2761C>T p.Gln921* [84
 c.2835−1G>C  [76,77
 c.2962C>T p.Gln988* [105
 c.2982insT p.Ala995Cysfs*16 [65
 c.3026delCT p.Phe1009Argfs*9 [76
 c.3048delT p.Phe1016Leufs*17 [86
 c.3113G>A p.Trp1038* and two altered spliced forms (p.Gly1028fs*2 and p.9991038del) [65,69,73,76,77,92a,107
 c.3113+5G>C r.28353113del279/p.Ala946fs [107
 c.3116delA p.Asn1039Ilefs*2 [65,69
 c.3202+1G>C  [77
 c.3362delG p.Gly1121Valfs*3 [106
 c.3549C>G p.Tyr1183* [65,69,77,82,107
Breast cancer cases in families with pancreatic cancer   
 c.72delG p.Arg26Glufs*7 [72
 c.1027C>T p.Gln343* [72
 c.1314delA p.Phe440Leufs*12 [72
 c.2920_2921delAA p.Lys974Glufs*5 [72
 c.2962C>T p.Gln988* [96
 c.3497delG p.Gly1166fs [72
 c.3549C>G p.Tyr1183* [96
Pancreatic cancer   
 c.172_175delTTGT p.Gln60Argfs*7 [66
 c.508_509delAG p.Arg170Ilefs*14 [95
 c.1240C>T p.Arg414* [95
 c.1314delA p.Phe440Leufs*12 [96
 c.2515−1G>T  [66
 c.3116delA p.Asn1039Ilefs*2 [66
 c.3201_3561del p.Met1067Ser1186del [94,110
 c.3256C>T p.Arg1086* [66
Ovarian cancer   
 c.172_175delTTGT p.Gln60Argfs*7 [76,91
 c.509_510delGA p.Arg170Ilefs*14 [67
 c.757_758delCT p.Leu253Ilefs*3 [88
 c.758insT p.Ser254Ilefs*3 [92
 c.1050delAACA p.Thr351Argfs*4 [88
 c.1240C>T p.Arg414* [92
 c.1479delC p.Thr494Leufs*67 [92
 c.2167delAT p.Met723Valfs*21 [92
 c.2323C>T p.Gln775* [77
Prostate cancer   
 c.1592delT p.Leu531Cysfs*30 [83
Fanconi's anaemia   
 c.395delT p.Val132Alafs*45 [64
 c.757–758delCT p.Leu253Ilefs*3 [64
 c.1653T>A p.Tyr551* [62
 c.1676–1677delAAinsG p.Gln559Argfs*2 [63
 c.2257C>T p.Arg753* [64
 c.2393_2394insCT p.Thr799Leufs*53 [64
 c.2521delA p.Thr841Glnfs*10 [64
 c.2962C>T p.Gln988* [64
 c.3113+5G>C r.28353113del279/p.Ala946fs [64
 c.3116delA p.Asn1039Ilefs*2 [64
 c.3294_3298delGACGA p.Lys1098Asnfs*23 [64
 c.3323delA p.Tyr1108Serfs*16 [64
 c.3350+4A>G r.3350insGCAG/p.Phe118fs [64
 c.3549C>G p.Tyr1183* [64
 c.3549C>A p.Tyr1183* [64

In a U.K. population study, Rahman et al. [65] found a truncating mutation frequency of 6.7% in families with male and female breast cancer compared with 1% in families with only female cases. They also estimated that mutations in PALB2 conferred an increased risk of breast cancer of 2.3-fold for women under 50 years of age and 1.9-fold for older women [65]. In the same year, Erkko et al. [70] identified a PALB2 founder mutation (c.1592delT) among Finnish breast cancer families, elevating the risk of developing breast cancer by 4-fold compared with controls. They reported a mutation frequency of 0.9% in unselected cases compared with 2.7% in family breast cancer cases [70]. In 2008, Erkko et al. [75] estimated the hazard ratio of the c.1592delT mutation and found a 6.1-fold increased risk equivalent to a 40% risk of having breast cancer before 70 years of age. They then evaluated that this risk decreased 4.2% each year (from 7.5-fold at 30 years old to 2.0-fold at 60 years old), thus supporting the previous evaluation of Rahman et al. [65]. In the U.S.A., Casadei et al. [76] studied familial breast cancer patients of Ashkenazi Jewish descent or unselected for any specific ancestry. In the latter population, they found a truncating mutation frequency of 3.4% and reported the increased breast cancer risk to be 2.3-fold by 55 years of age and 3.4-fold by 85 years of age. The increased risk was even higher, 5.3-fold, in a study conducted by Tishkowitz et al. [77] on Danish and American populations. That study was, however, limited by a small sample size.

In summary, three studies (Rahman et al. [65], Erkko et al. [75] and Casadei et al. [76]) have estimated the increased risk of breast cancer conferred by PALB2 mutations to be approximately 2-fold by the age of 55 years. However, they differ in the assessment of this increase before and after this age. This might suggest that the mutations have different consequences on genomic stability, thus leading to different levels of risk. So far, only two studies (Garcia et al. [69] and Casadei et al. [76]) have identified loss of heterozygosity of PALB2 in breast cancer tumours. To our knowledge, no other studies have reported this alteration in breast [67,70,71,78] or ovarian [79] tumours.

In a 2009 screen of breast cancer families unselected for male breast cancer, Garcia et al. [69] found a novel mutation, c.1056_1057delGA (p.Lys353Ilefs*7), in a Spanish family that included one male breast cancer case, for a mutation frequency of 1%. This frequency was increased to 9% when they looked at families with both male and female breast cancers (11 cases) specifically, suggesting that mutations in PALB2 might confer a higher risk of male breast cancer. However, no obvious PALB2 mutation was found by Blanco et al. [80] out of 131 Spanish breast/ovarian cancer families with at least one male breast cancer case. Instead, they found one large rearrangement [c.2587-?_3201 +?del (exons 7–11)] in one breast cancer patient, accounting for a frequency of 0.75% in this subpopulation. In The Netherlands, Adank et al. [81] identified the mutation c.509_510delGA (already identified in breast and ovarian cancer, p.Arg170Ilefs*14) in one male breast cancer patient among 110 (0.9%) cases with a family history of ovarian, pancreatic, or female or male breast cancer. Remarkably, this patient also had melanoma. An American study by Ding et al. [82] reported one male breast cancer patient among 97 carrying a mutation causing the protein variant p.Tyr1183* (c.3549C>G); this patient also suffered from melanoma. Interestingly, the same mutation had already been reported in a female breast cancer patient with melanoma [65]. This mutation had also been described in FA [64]. Ding et al. [82] also identified a non-truncating mutation predicted to be pathogenic in another male breast cancer case and therefore proposed that the frequency of deleterious PALB2 mutation was between 1 and 2% in male breast cancer.

Focusing on male patients, mutations of PALB2 have also been investigated in prostate cancer. To date, only one mutation (c.1592delT; p.Leu531Cysfs*30) has been found [83], this mutation being known to be a founder mutation of the Finnish population and associated with a high risk of developing breast cancer (hazard ratio estimated to be 6.1-fold by Erkko et al. [70]).

From these studies, it seems that PALB2 mutations in male breast cancer occur with a frequency (0.75–1%) that is actually close to that for unselected female breast cancer (0.4–2%). However, one should bear in mind that the rarity of male breast cancer makes it difficult to generate any conclusive evaluation of this frequency. These studies also highlighted a possible role for PALB2 mutations in prostate and skin cancer.

Mutations of PALB2 in ovarian cancer

Several teams have investigated the presence of PALB2 mutations in ovarian cancer while analysing breast cancer mutations. Garcia et al. [69] found the mutation c.1056–1057delGA (p.Lys353Ilefs*7) in one Spanish family with cases of breast and ovarian cancer. In Italy, Balia et al. [78] identified the mutation c.1317delG (p.Phe440Leufs*12) in 1.05% of families with a similar history. The study by Bogdanova et al. [84] included two cases with a personal history of ovarian cancer, but the previously identified mutations were not found. Similar observations were reported by Wong-Brown et al. [85] for two Australian cases of ovarian cancer. Nonetheless, the mutation c.3113G>A (p.Trp1038* and two other spliced forms deleted for exon 10) was identified in a patient with a family history of breast and ovarian cancer. Another rare truncating mutation that could be linked to ovarian cancer, c.1479delC (p.Thr494Leufs*67), was found subsequently in the same conditions by Zheng et al. [86] in unselected African Americans. The following year, Teo et al. [87] re-identified the c.3113G>A mutation in 0.92% of their Australian patients at high risk of breast and/or ovarian cancer.

When teams looked only at ovarian cancer cases, only a few mutations were discovered. Dansonka-Mieskowska et al. [67] found the mutation c.509_510delGA (p.Arg170Ilefs*14) in 0.6% of ovarian cancer cases compared with 0.08% in controls in the Polish population. Walsh et al. [88] identified two mutations in ovarian cancer cases: c.757_758delCT (p.Leu253Ilefs*3), also known in FA [64] and breast cancer [76], and c.1050delAACA (p.Thr351Argfs*4), which was also later described in breast cancer [89]. Tischkowitz et al. [79] found one carrier of the c.2323C>T mutation (p.Gln775*) in 491 French Canadian women with ovarian cancer or low malignant potential tumours. However, this mutation had been identified previously in French Canadian breast cancer patients [90] with a frequency of 0.56% in unselected cases and 2% in cases selected based on family history. In their study, Tischkowitz et al. [79] also re-identified the c.2323C>T mutation in 2.1% of families with hereditary breast cancer. The Russian population study by Prokofyeva et al. [91] identified the truncating mutation c.172_175delTTGT (p.Gln60Argfs*7) (with a frequency of 0.4%), which they also found in two breast cancer cases. The same mutation had been reported previously in pancreatic cancer. More recently, in a large-scale exome-wide analysis performed to identify germline and somatic mutations in 429 ovarian cancer from woman with diverse ethnic origins, five truncating mutations were found in PALB2, four of them being germline mutations and including one never reported before: c.2167delT (p.Met723Valfs*21) [92].

In summary, nine truncating mutations of PALB2, eight recurrent notably in breast cancer, have been found so far in ovarian cancer cases including c.172_175delTTGT (Prokofyeva et al. [91]), c.509_510delGA (Dansonka-Mieskowska et al. [67]), c.757_758delCT, c.1050delAACA (Walsh et al. [88]), c.2323C>T (Tischkowitz et al. [79]). Four other mutations have been identified in cases with breast and ovarian cancer family history: c.1056_1057delGA (Garcia et al. [69]), c.1479delC (Zheng et al. [86]), c.1517delG (Balia et al. [78]) and c.3113G>A (Wong et al. [92a] and Teo et al. [87]).

PALB2 mutations in pancreatic cancer

A few years ago, the PALB2 gene was identified as a susceptibility gene for FPC (familial pancreatic cancer), ranking second after BRCA2 [66]. The Jones group identified distinct PALB2-truncating mutations in three out of 96 (3.1%) American patients with FPC: c.172_175delTTGT, also found in breast and ovarian cancer and identified later by Villarroel et al. [93], and c.3116delA described previously in breast cancer patients, and c.3256C>T. The patient harbouring the c.172–175delTTGT mutation also presented a somatic mutation in his tumour at a canonical splice site for exon 10 (IVS10+2C>T). This same mutation (c.172_175delTTGT with biallellic inactivation through IVS10+2C>T) was later identified in tumours of a male pancreatic cancer patient with a family history of pancreatic cancer [93]. In a larger screen of pancreatic cancer cases (254 individuals), Tischkowitz et al. [94] reported a large deletion (del from exon 12–2.7 kb to exon 13+1.8 kb) in one pancreatic cancer patient who had been diagnosed initially with breast cancer.

In 2010, Slater et al. [95] identified truncating mutations in three out of 81 (3.7%) European pancreatic cancer families, each of which had a breast cancer history. Of the three mutations, one had already been reported in FPC families by Jones et al. [66] (c.3116delA; p.Asn1039Ilefs*2), another was associated with breast cancer occurrence (c.1240C>T; p.Arg414*) and a new mutation (c.508_509delAG; p.Arg170Ilefs*14) was predicted to lead to the production of a protein similar to the product of another mutation reported in breast and ovarian cancer: c.509_510delGA.

Peterlongo et al. [72] succeeded in finding one mutation (c.1314delA; p.Phe440Leufs*12, which is already known in breast cancer) in a patient who had developed multiple cancers, one of which was pancreatic. They also identified three mutations [c.72delG (p.Arg26Glu*7), c.1027C>T (p.Gln343*) and c.3497delG (p.Tyr1183*)] in breast cancer families with at least one case of pancreatic cancer. In similar families, Hofstatter et al. [96] found the mutation c.2962C>T (p.Gln988*) and again c.3549C>G (p.Tyr1183*), which is already known in FA [64] and breast cancer [65] respectively.

In summary, seven mutations conferring an increased risk of pancreatic cancer have been identified, but only two appear so far to be pancreatic cancer-specific, i.e. c.508_509delAG and c.3256C>T, and only one leads to a unique variant protein (c.3256C>T; p.Arg1086*). It is also interesting to note that only two large rearrangements have been found. A study by Blanco et al. [80] on breast and ovarian cancer families with male breast cancer cases reported c.2587-?_3201 +?del (exons 7–11) and Tischkowitz et al. [94] found, in pancreatic cancer patients, c.del from exon 12–2.7 kb to exon 13+1.8 kb.

Insights from animal models

Previous attempts in mouse modelling PALB2-associated breast cancer have shown that biallellic deletion of Palb2, by gene trap technology or exon deletion, is not compatible with life and leads to embryonic lethality between E8.5 (embryonic day 8.5) and E12.5, with growth retardation and severe morphological abnormalities from E7.5 [9799]. This lethality is believed to result from increased apoptosis, unlike that caused by Brca1 or Brca2 deletion, which has been attributed mainly to hypoproliferation [98]. Interestingly, p21 expression level was increased 6-fold in Palb2-knockout mice, whereas levels of Brca1, Brca2, Rad51 and Trp53 were normal [97]. The embryonic lethality could be slightly delayed by the co-deletion of Trp53 or p21, but not rescued [98,99]. Heterozygous animals, however, were revealed to be viable, fertile and presented no developmental retardation or abnormality, providing an avenue to study tumour development subsequent to Palb2 mutations in vivo. Common to previous reports, the Palb2+/− mice showed no spontaneous tumour phenotype [97,98]. The cross of Palb2 heterozygous mice with Trp53-knockout mutants had no effect on tumour development. A reduction in Palb2 mRNA levels was confirmed in the progeny, suggesting against Palb2 being a haploinsufficient tumour suppressor [98,100]. Interestingly, analysis of mice heterozygous for Palb2 and Brca2 deletion revealed no genetic interaction between these genes in development and tumorigenesis, as mice were viable, fertile and did not harbour predisposition to spontaneous tumours [98].

In 2013, Bowman-Colin et al. [99] generated a breast cancer model in which Palb2 and Trp53 were co-deleted in the mouse mammary gland. Breast tumours developed faster in Palb2/Trp53 double conditional mice than in Trp53-null mice (t½=192 days compared with 320 days), with a latency similar to those observed for deletion of Brca1 or Brca2 on such Trp53 mutant background. As described for BRCA1 and BRCA2 mutant cancers, PALB2 tumours were found to be defective in RAD51 focus formation, in agreement with the known role of PALB2 in HR-mediated DSB repair. However, several genomic features distinguished Palb2/Trp53 breast tumours from Brca1/Trp53 and Brca2/Trp53, suggesting that PALB2 exerts functions that are non-overlapping with those of the BRCA proteins. Of note, no haploinsufficiency was detected with this model either and heterozygosity did not impair RAD51 foci formation, suggestive of an intact PALB2 HR function. Moreover, the strategy used in this model to target the Palb2 gene (deleting exons 2 and 3) comes with the possibility of producing a protein that is truncated before the WD40 repeat domain and therefore has lost its BRCA2-interating domain [99].

Taken together, these studies indicate that PALB2 is essential for early embryonic development in mice and might not be a haploinsufficient tumour suppressor. Interestingly, they also raised the question of whether truncated PALB2 could retain some activity in HR, independently of its interaction with BRCA2.

Functional studies of disease-related mutations

Important clues to a better understanding of how heterozygous truncating mutations in PALB2 can lead to cancer have been provided by functional studies. Noteworthy are the mutations c.229delT, c.1592delT and c.2521delA, which have been introduced into PALB2 cDNA, resulting in the expression of truncated proteins (p.Cys77Valfs*100, p.Leu531Cysfs*30 and p.Thr841Glnfs*10 respectively), with markedly reduced BRCA2-binding capacity [70,71]. Consistent with this, expression of any of these three mutants failed to rescue HR in cells depleted of PALB2 by RNAi, or the sensitivity to MMC of PALB2-deficient cells, suggesting a PALB2 functional inactivation. Owing to the low incidence of loss of heterozygosity in PALB2 mutation carriers, it has been suggested that PALB2 is likely to contribute to carcinogenesis through haploinsufficiency and/or a dominant-negative effect [79]. The possibility of a dominant-negative effect has been ruled out for the c.229delT mutation, whereas c.1592delT proved to be a true loss-of-function mutation [70,71].

Similar studies were performed with the mutation c.1653T>A (p.Tyr551*) first identified in an FA patient [62] and then in a breast cancer patient [76]. Xia et al. [62] demonstrated that EUFA1341 lymphoblasts from an FA patient carrying the c.1653T>A mutation harboured a decreased level of BRCA2. EUFA1341 fibroblasts presented a mislocalization of BRCA2, compromised RAD51 foci formation and a higher sensitivity to MMC treatment. Complementation of these cells with a vector overexpressing PALB2-Tyr551* failed to rescue the sensitivity, in contrast with the overexpression of a PALB2 exon-4-deleted protein identified in reverted EUFA1341. This latter result suggests that a PALB2 with a large internal deletion can be functional, whereas a PALB2 with its C-terminal part deleted is not. In 2013, Park et al. [45] showed that p.Tyr551* did not interact with BRCA2 or RAD51C, and was deficient in its interaction with RAD51. Interestingly, the team also reported that cancer-related missense mutations affecting the WD40 domain also showed compromised interaction with BRCA2, RAD51 and RAD51C. Taken together, these results illustrate the importance of the WD40 domain and its integrity.

Studies on lymphoblastoid cell lines derived from heterozygous PALB2 c.1592delT mutation carriers have highlighted the hypersensitivity of the cells to MMC and, more recently, defects in DNA replication and damage response that could drive cancer development [83,101]. These defects are manifested by aberrant DNA replication dynamics, increased ATR kinase protein levels and G2/M-phase checkpoint maintenance problems associated with genomic instability. As in most cases, the analysis conducted by Nikkilä et al. [101] revealed no loss of heterozygosity in PALB2 breast tumours. Mutation carrier cells harboured a decreased level of PALB2 with detectable levels of the highly unstable truncated protein product (10% of full-length PALB2), consistent with a fraction of the mutant transcript being able to escape to NMD (nonsense-mediated decay).

These findings by Nikkilä et al [101] were in line with a mechanism in which the haploinsufficiency of PALB2, in combination with a possible dominant-negative effect of the c.1592delT truncated protein product, could drive tumorigenesis without requiring loss of heterozygosity. Supporting this idea, several other teams found that mutation in PALB2 led to transcripts only partially subjected to NMD. Casadei et al. [76] had previously shown, by studying transcripts from patients carrying the c.3113G>A mutation, that this mutation leads to three kinds of transcripts: one with an in-frame 117 bp deletion (56%), one with an out-of-frame 31 bp deletion (40%) and one with an immediate stop codon at position 1038 (4%, p.Trp1038*). Teo et al. [87] also found that c.3113G>A produced the two same altered splicing transcripts, both leading to a deletion of exon 10 (p.Gly1028fs*3 and p.Gly1000_Gly1038del), but did not identify the transcripts leading to p.Trp1038*. However, they found two other mutations (c.1947insA and c.2982insT) that produced transcripts also targeted by NMD, but still harbouring expression of the final protein. The data from Nikkilä et al. [101] were, however, in conflict with previous studies in Palb2-knockout mice showing that Palb2 might not be a haploinsufficient tumour suppressor, leaving some doubts as to the exact mechanism of PALB2-driven tumorigenesis. It should also be considered that the negative effect or the loss of function of truncated PALB2 could actually be due to as yet uncovered functions of PALB2 (chromatin remodelling, ROS regulation, etc).

Using PALB2 defect as a therapeutic strategy

Depletion of PALB2 using siRNA has been reported to sensitize cells to various inhibitors of PARP, such as olaparib, veliparib, rucaparib and BMN673 [36,102], through a synthetic lethal effect. Some of these drugs have already reached Phase II or III of clinical trials for BRCA1/2 ovarian cancer. PARP inhibitors thus represent a potentially promising therapy in the context of PALB2-mutated cancers. This underscores the need for PALB2 genetic testing so that all candidate patients can benefit from such targeted therapies.

The concept of synthetic lethality (Figure 3), based on PALB2, could be also used with RAD52. In light of this, Powell and co-workers investigated whether depletion of RAD52 could possess synthetic lethality as with other HR genes [103]. Control experiments revealed little impact on cell growth and plating efficiency for RAD52-depleted cells. Strikingly, when combined with BRCA2, BRCA1 and PALB2, a severe reduction in plating efficiency was observed [103,104]. Loss of RAD52 led to a reduction in radiation-induced RAD51 foci formation and DSB-induced HR in the absence of BRCA2. In the light of this work, inhibition of RAD52 could be an alternative synthetic lethal strategy in PALB2-deficient cells.

Synthetic lethal strategy as a targeted cancer therapy

Figure 3
Synthetic lethal strategy as a targeted cancer therapy

Defect of one cellular pathway (pathway B) is not lethal for a cell, but the inhibition of a second pathway (pathway A) in this pathway-B-defective cell leads to cell death.

Figure 3
Synthetic lethal strategy as a targeted cancer therapy

Defect of one cellular pathway (pathway B) is not lethal for a cell, but the inhibition of a second pathway (pathway A) in this pathway-B-defective cell leads to cell death.

How could PALB2 mutations lead to cancer development? It was reported recently that heterozygous mutations in PALB2 cause DNA replication and damage response defects. Using a DNA fibre assay technique, it was found that PALB2 haploinsufficiency causes excessive origin firing and a shorter distance between consecutive replication forks. Moreover, PALB2 affected ATR levels and the DNA replication stress response. PALB2 mutation carrier cell lines also show elevated ATR protein (but not phosphorylation) levels, and the majority of these lines display an aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These data explain how germline defects in PALB2 connect to cancer development and hereditary predisposition to the disease [101]. Clearly, there are many more facets of PALB2 waiting to be revealed in the future.

Abbreviations

     
  • ATR

    ataxia telangiectasia- and Rad3-related

  •  
  • BRCA

    breast cancer early-onset

  •  
  • ChAM

    chromatin-association motif

  •  
  • DSB

    DNA double-strand break

  •  
  • E

    embryonic day

  •  
  • FA

    Fanconi’s anaemia

  •  
  • FPC

    familial pancreatic cancer

  •  
  • HD

    helix domain

  •  
  • HR

    homologous recombination

  •  
  • ICL

    interstrand cross-link

  •  
  • KEAP1

    Kelch-like ECH-associated protein 1

  •  
  • MMC

    mitomycin C

  •  
  • NHEJ

    non-homologous end-joining

  •  
  • NMD

    nonsense-mediated decay

  •  
  • NRF2

    nuclear factor-erythroid 2-related factor 2

  •  
  • OB

    oligonucleotide-binding

  •  
  • PALB2

    partner and localizer of BRCA2

  •  
  • PARP

    poly(ADP-ribose) polymerase

  •  
  • Polη

    polymerase η

  •  
  • ROS

    reactive oxygen species

  •  
  • RPA

    replication protein A

We thank Isabelle Brodeur and Helen Rothnie for comments on this paper. J.-Y.M. is a FRQS (Fonds de Recherche du Québec, Santé) Chercheur National Investigator.

FUNDING

This work was supported by the CIHR (Canadian Institutes of Health Research) (to J.-Y.M.).

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