Most of the core components of the archaeal chromosomal DNA replication apparatus share significant protein sequence similarity with eukaryotic replication factors, making the Archaea an excellent model system for understanding the biology of chromosome replication in eukaryotes. The present review summarizes current knowledge of how the core components of the archaeal chromosome replication apparatus interact with one another to perform their essential functions.

Introduction

In all forms of cellular life, chromosomal DNA replication requires the complex interplay of a large number of essential and non-essential protein factors in a temporally and spatially co-ordinated manner. Highly efficient high-fidelity chromosome replication is vital for maintaining the integrity of the genetic information and for the avoidance of genetic disease.

The Archaea, the third domain of life on Earth, have attracted considerable interest as a model for understanding the fundamental processes of eukaryotic chromosome replication, as many factors central to the processes of replication in eukaryotes have orthologues in the Archaea, consistent with the shared evolutionary history of the eukaryotic and archaeal domains [1]. To date, a significant amount of effort has gone into identifying, purifying (often in recombinant form) and characterizing individual archaeal replication factors. In contrast, our understanding of how these individual factors interact with one another during the replication processes is still fragmentary. In the present review, current knowledge of protein–protein interactions in the core archaeal chromosomal DNA replication machinery is summarized and the prospects for future progress in this important area are highlighted.

The core archaeal replisome: an overview

Approx. 20–25 proteins have been identified that are likely to have some role to play in chromosome replication in archaeal cells, 10–15 of which can be considered to be core components of the replication machinery (Table 1) [1]. These core proteins were mostly identified on the basis of their sequence similarity to eukaryotic replication factors and are thought to be essential for replication to proceed, although it is important to stress that direct evidence for this is generally lacking. The remaining (non-core) proteins include, for example, enzymes involved in TLS (translesion DNA synthesis), such as the family Y DNA polymerases [2], or in replication fork remodelling, such as the Hel308 helicase [3]. In the present review, only interactions between core components are considered.

Table 1
Core components of the archaeal replisome
Component 
Archaea Eukarya Comments 
Cdc6/Orc1 Cdc6 and ORC In eukaryotes, the six-subunit ORC binds replication origins and acts as a landing pad for Cdc6 which catalyses loading of the MCM complex on to DNA; five of the six eukaryotic ORC subunits are related to one another and to Cdc6 [9]. In the Archaea, the functions of ORC and Cdc6 appear to reside in a single protein: Cdc6/Orc1 [11
MCM MCM Catalytic core of the replicative helicase; heterohexameric in eukaryotes, homohexameric in most archaea [13
GINS GINS Heterotetrameric in eukaryotes (Sld5, Psf1, Psf2 and Psf3); dimer of dimers in some archaea (Gins51 and Gins23 dimers), while believed to be homotetrameric in others (Gins51 tetramer) [18
RPA/SSB RPA Single-stranded DNA-binding factor: heterotrimeric in eukaryotes, various configurations in archaea [66
Primase Primase Dimeric primase with catalytic PriS and non-catalytic PriL subunits; an integral part of Pol A in eukaryotes, not believed to be polymerase-associated in archaea [39
PolB – Monomeric family B polymerase, related to catalytic subunit of eukaryotic replicative polymerases [1
PolD – Dimeric family D polymerase with polymerase (PolD2) and nuclease (PolD1) subunits found only in euryarchaea [1
RFC RFC Heteropentameric in eukaryotes (one large, four small subunits); various configurations in archaea, but apparently all pentameric with one large subunit and four small subunits, the latter encoded by one or two genes [24,45
PCNA PCNA Sliding clamp; homotrimeric in eukaryotes and either homo- or hetero-trimeric in archaea [1,22
Fen1 Fen1 Endonuclease involved in Okazaki fragment processing; monomeric [1
DNA ligase DNA ligase I ATP-dependent ligase involved in Okazaki fragment joining; monomeric [1
Component 
Archaea Eukarya Comments 
Cdc6/Orc1 Cdc6 and ORC In eukaryotes, the six-subunit ORC binds replication origins and acts as a landing pad for Cdc6 which catalyses loading of the MCM complex on to DNA; five of the six eukaryotic ORC subunits are related to one another and to Cdc6 [9]. In the Archaea, the functions of ORC and Cdc6 appear to reside in a single protein: Cdc6/Orc1 [11
MCM MCM Catalytic core of the replicative helicase; heterohexameric in eukaryotes, homohexameric in most archaea [13
GINS GINS Heterotetrameric in eukaryotes (Sld5, Psf1, Psf2 and Psf3); dimer of dimers in some archaea (Gins51 and Gins23 dimers), while believed to be homotetrameric in others (Gins51 tetramer) [18
RPA/SSB RPA Single-stranded DNA-binding factor: heterotrimeric in eukaryotes, various configurations in archaea [66
Primase Primase Dimeric primase with catalytic PriS and non-catalytic PriL subunits; an integral part of Pol A in eukaryotes, not believed to be polymerase-associated in archaea [39
PolB – Monomeric family B polymerase, related to catalytic subunit of eukaryotic replicative polymerases [1
PolD – Dimeric family D polymerase with polymerase (PolD2) and nuclease (PolD1) subunits found only in euryarchaea [1
RFC RFC Heteropentameric in eukaryotes (one large, four small subunits); various configurations in archaea, but apparently all pentameric with one large subunit and four small subunits, the latter encoded by one or two genes [24,45
PCNA PCNA Sliding clamp; homotrimeric in eukaryotes and either homo- or hetero-trimeric in archaea [1,22
Fen1 Fen1 Endonuclease involved in Okazaki fragment processing; monomeric [1
DNA ligase DNA ligase I ATP-dependent ligase involved in Okazaki fragment joining; monomeric [1

Replication of archaeal chromosomes is initiated at one or more replication origins [48]. These specific DNA regions are bound by proteins of the Cdc6/Orc (origin recognition complex) 1 family [9]. Almost all sequenced archaeal genomes encode at least one Cdc6/Orc1 family member, with some (haloarchaeal) species encoding more than ten. These proteins comprise an N-terminal AAA+ (ATPase associated with various cellular activities) domain [10] and a C-terminal wH (winged helix) DNA-binding domain [11] and function to load the MCM (minichromosome maintenance) complex on to DNA. In eukaryotic cells, Cdt1 participates in this process; in the archaea, a protein with similarity to Cdt1 [called WhiP (wH initiator protein)] has been implicated in replication initiation in certain species, but is not widely conserved [8].

MCM is believed to be the replicative helicase in eukaryotic and archaeal cells [12]. Most archaea encode a single MCM protein that forms a homohexameric complex [13], but, as with the Cdc6/Orc1 proteins, some species encode additional MCM homologues that may form heteromultimers [14,15]. Eukaryotic MCM is a heterohexamer whose active form is found in a complex [the CMG (Cdc45/MCM/GINS) complex] with Cdc45 and the heterotetrameric GINS complex [16,17]. Cdc45 has no known orthologue in the Archaea, but GINS proteins are found in all archaeal species [18]. It is thought that GINS may play a role either as a key structural component of the MCM complex or as a regulator of MCM activity [19]. Although the structures of several archaeal MCM proteins have been solved, no MCM–GINS co-crystal structures are known [20].

Once the DNA at the origin is unwound, additional components assemble to form the replisome present at the replication fork [1]. These events, and how they are regulated, represent one of the most poorly understood areas of archaeal replication. It is striking that the key regulatory factors that function at this stage in the initiation process in eukaryotic cells, Sld2, Sld3 and Dpb11, are not found in archaea. However, it should be noted that these proteins are very poorly conserved at the protein sequence level across eukaryotic species, making it highly unlikely that archaeal orthologues, should they exist, would be identified purely by sequence similarity.

Once the origin DNA is unwound, new DNA synthesis requires the action of primase and at least one DNA polymerase enzyme [1]. Primase is responsible for the synthesis of the short RNA segments that prime the synthesis of the leading strand and each Okazaki fragment on the lagging strand. The primer is then extended by the action of a DNA polymerase. To date, the identity of the polymerases involved at the fork, and their precise roles, remains unclear [1]. All archaeal species encode at least one family B DNA polymerase (PolB), while, in addition to this, the euryarchaea also encode a dimeric family D enzyme (PolD). Genetic analysis in the haloarchaea has shown both PolB and PolD to be essential for cell viability [21].

Both PolB and PolD interact with the sliding clamp PCNA (proliferating-cell nuclear antigen) [1]. This ring-shaped trimer encircles double-stranded DNA, tethering the polymerase and thereby enhancing polymerase processivity [22]. Interactions between PCNA and a wide range of factors have been identified [23]. Loading of PCNA on to DNA (a process that requires the PCNA ring to be enzymatically opened and closed around the DNA duplex) is carried out in an ATP-dependent manner by RFC (replication factor C), a pentameric complex of AAA+ proteins [24].

Once new DNA synthesis is complete, when the nascent 3′-end of an Okazaki fragment encounters the 5′-end of the previously synthesized Okazaki fragment, the ends of the nascent DNA are processed and joined by various enzymes including the nucleases Fen1 (flap endonuclease 1) and RNaseHII, and DNA ligase [1].

Screening for interacting proteins

Building up a comprehensive picture of the architecture of the replication machinery requires a detailed understanding of interactions that take place between its components. The ease with which many archaeal proteins can be purified in recombinant form and analysed biochemically, in isolation, has meant that relatively little attention has been paid to probing protein–protein interactions between well-characterized components or to screening for novel interacting components.

To date, there has been only a single report describing a systematic screening approach to define the protein–protein interaction network of the archaeal replisome [25]. Using the Y2H (yeast two-hybrid) system, with candidate Archaeoglobus fulgidus replication factors as baits, a number of novel interactions between known or suspected replisome components were identified (Figure 1) [25]. Several of the prey proteins identified in these screens were then used as baits in a second round of screening. The baits used included PCNA, PolB, the small and large subunits of RFC, two putative single-stranded DNA-binding factors RPA (replication protein A) 26 and RPA36, and the PolD subunits PolD1 and PolD2 [25]. Among the interactions identified in this way are interactions between PCNA and PolB, RNaseHII, the large subunit of RFC, Fen1 and the polymerase subunit of PolD (Figure 1). In each of these cases, PCNA binding was mediated via a PIP (PCNA-interacting protein) motif (discussed further below). An interaction was also detected between PCNA and RPA36 that does not seem to involve a PIP motif [25] (Figure 1). In addition to this Y2H screening, a screen of immobilized peptides for novel PCNA-interacting sequences has also been carried out [26], leading to the identification of novel PCNA-binding proteins, including a novel structure-specific DNA endonuclease, NucS [27].

Summary of protein–protein interactions

Figure 1
Summary of protein–protein interactions

Schematic representation of protein–protein interactions between core archaeal replisome components. Interactions specific to the S. solfataricus Gins51 and Gins23 proteins are indicated as 51 or 23 respectively; interactions specific to the S. solfataricus PCNA1, PCNA2 and PCNA3 proteins are indicated as 1, 2 and 3 respectively. See the text for details and references.

Figure 1
Summary of protein–protein interactions

Schematic representation of protein–protein interactions between core archaeal replisome components. Interactions specific to the S. solfataricus Gins51 and Gins23 proteins are indicated as 51 or 23 respectively; interactions specific to the S. solfataricus PCNA1, PCNA2 and PCNA3 proteins are indicated as 1, 2 and 3 respectively. See the text for details and references.

Interactions involving Cdc6/Orc1 proteins and MCM

As described above, Cdc6/Orc1 is a multidomain protein comprising an N-terminal AAA+ module and a C-terminal wH module that binds replication origin DNA in a sequence-specific manner [11]. Many archaeal species encode multiple Cdc6/Orc1 homologues. Several studies have reported direct interactions between Cdc6/Orc1 homologues and the MCM helicase detected by a variety of methods, including Y2H, far-Western analysis, co-immunoprecipitation and gel filtration, and from a variety of species, including Methanothermobacter thermoautotrophicus [2830], Thermoplasma acidophilum [31,32], Pyrobaculum aerophylum [30] and Sulfolobus solfataricus [33] (Figure 1).

In the case of the M. thermoautotrophicus, Y2H assays have been used to demonstrate that the wH domain of the Cdc6–1 protein binds to the NTD (N-terminal domain) of MCM [30]. Structural analysis of the MCM NTD identified three subdomains designated A, B and C [34]. Deletion analysis indicates that A and B are not required for interaction with Cdc6–1, but that C is. Weak binding of Cdc6–2 to MCM was also detected, using a far-Western assay, but this did not appear to involve the Cdc6–2 wH domain [30]. Pull-down assays with recombinant proteins confirmed the MCM–Cdc6–1 and MCM–Cdc6–2 interactions. The biochemical consequences of Cdc6/Orc1 addition on the helicase activity of MCM are different in different organisms. In the case of M. thermoautotrophicus and S. solfataricus, Cdc6/Orc1 binding inhibits MCM [30,33,35], whereas in the case of T. acidophilum, a substantial stimulation is seen [31,32]. Whether the observed differences reflect differences in Cdc6/Orc1 and MCM function inside the cell is unclear.

As well as interacting with MCM, evidence from Y2H analysis points to an interaction between Pyrococcus furiosus Cdc6/Orc1 and Gins51, one of the subunits of the GINS complex [36] (Figure 1). Further analysis of this interaction is yet to be reported. In addition, data from ELISA pull-down and far-Western analysis points to a direct interaction between the S. solfataricus MCM complex and the single-stranded DNA-binding factor RPA/SSB (single-stranded DNA-binding protein) that stimulates the in vitro activity of the helicase on different templates [37].

Interactions between MCM, GINS and primase

In eukaryotic cells, the active form of the replicative helix is the CMG complex [16,17]. No archaeal homologues of Cdc45 have been identified, but genes encoding GINS proteins are found in all species examined [18]. To date, however, GINS complexes have been characterized from S. solfataricus [38] and P. furiosus [36] only. In both cases, the complexes are tetrameric in nature, comprising two molecules of Gins23 and two of the related Gins51 proteins. In both S. solfataricus and P. furiosus, Gins23 is seen to interact with MCM in Y2H assays and in co-immunoprecipitation experiments using extracts prepared from exponentially growing archaeal cells [36,38] (Figure 1). In the case of S. solfataricus, Gins23 binding has been mapped to the MCM NTD. Whether MCM binds to the A- or B-domain of Gins23, or both, remains to be seen. Interestingly, the effect of GINS binding on MCM activity differs in the two organisms: in P. furiosus, addition of GINS stimulates MCM helicase activity in vitro [36], whereas in S. solfataricus, no such effect is seen [38]. Further analysis is clearly required to resolve these differences and to map better the site of interaction between the complexes. In addition, it is striking that there are many archaeal organisms that appear to encode a Gins51 protein only [18]. Although the possibility exists that current bioinformatic methods are insufficiently sensitive to detect highly divergent Gins23 proteins, this raises important questions about how, or if, MCM and GINS interact in these organisms. Resolving this uncertainty is an important goal.

Three other interactions involving GINS have been reported (Figure 1). First, in Y2H and recombinant protein pull-down assays, S. solfataricus Gins23 has been shown to interact with both subunits of the archaeal primase, PriS and PriL [38]. Both primase subunits are multidomain proteins [39]: PriS comprises the catalytic domain and a C-terminal domain that, in many species, is similar in structure to the B-domain of the GINS proteins [40], whereas PriL comprises a non-catalytic domain and a C-terminal Fe–S cluster co-ordinated by four conserved cysteine residues that is essential for primer synthesis [41]. How exactly GINS interacts with primase is not known, neither is it known what effect this interaction has on the cellular function of either partner. Secondly, as noted above, evidence from Y2H analysis points to an interaction between P. furiosus Gins51 and Cdc6/Orc1 [36]. Again, the function of this interaction is unclear, although targeting of GINS to replication origins is one possibility. Thirdly, in S. solfataricus, the GINS complex forms a stable association with RecJdbh, a non-conserved protein containing a RecJ-like DNA-binding domain [38]. In Y2H, RecJdbh interacts with Gins51, but, as with the Gins23–primase and Gins51–Cdc6/Orc1 interactions, the function of the Gins51–RecJdbh interaction is not known.

Interactions between primase and RFC

RFC is the enzyme complex that loads the ring-shaped sliding clamp PCNA on to double-stranded DNA at the primer–template junction in an ATP-dependent manner [24]. Eukaryotic RFC is a heteropentameric complex comprising one large subunit and four small subunits. All five subunits are related to one another and are members of the AAA+ family [10]. In the archaea, small and large RFC subunits (RFC-S and RFC-L respectively) can be readily identified by bioinformatic means. In certain species, including S. solfataricus [42] and P. furiosus [43], one RFC-L subunit assembles with four identical RFC-S subunits to form functional RFC. In others, such as Methanosarcina acetivorans, RFC comprises one RFC-L subunit, three RFC-S1 subunits and one RFC-S2 subunit, the latter pair being encoded by distinct genes [44,45].

The primer bound by RFC is synthesized by primase. In Y2H assays using S. solfataricus proteins, PriS interacted strongly with RFC-S, whereas PriL interacted weakly with both RFC-S and RFC-L [46] (Figure 1). The PriS–RFC-S interaction was confirmed by co-immunoprecipitation of native PriS and RFC-S proteins from S. solfataricus cell extracts and by co-immunoprecipitation of recombinant proteins. The PriL–RFC-S interaction was also seen when recombinant proteins were co-immunoprecipitated. Using the Y2H system, the interaction between PriS and RFC-S was mapped to the N-terminal (catalytic) domain of PriS [46]. Additional biochemical analysis showed that RFC was able to inhibit primer synthesis by primase, apparently by decreasing the affinity of primase for its template, while simultaneously stimulating dinucleotide formation, a reaction known to be able to occur in the absence of a DNA template [47]. This effect is probably modulated via the PriS–RFC interaction, as dinucleotide formation by PriS alone is also stimulated by RFC. How these changes to the activity of the enzyme contribute towards primase function at the replication fork remains to be seen. As described in the following section, RFC also interacts directly with the sliding clamp PCNA.

Interactions with PCNA

In eukaryotic cells, the sliding clamp PCNA is a homotrimeric ring-shaped complex that encircles double-stranded DNA to act as a processivity factor for the replicative polymerases and as a platform on to which diverse DNA-processing enzymes are assembled [22]. Archaeal PCNA complexes fall into two groups. In the euryarchaea, as in eukaryotes, PCNA is homotrimeric; the crystal structures of several euryarchaeal PCNA are available, including those from A. fulgidus [48], P. furiosus [49,50] and Haloferax volcanii [51,52]. In contrast, crenarchaeal organisms encode multiple PCNA proteins with the potential to form both homo- and hetero-trimeric complexes [53]; the structure of a heterotrimeric S. solfataricus PCNA has been solved [54,55].

Interactions between the PCNA and its binding partners are the best understood of all the interactions involving core replisome components, not least because the majority of proteins known to interact with PCNA do so via a conserved protein sequence motif [56]. This short peptide sequence, the PIP motif, binds to a conserved hydrophobic pocket on the surface of the PCNA monomer [57]. PIP motifs are typically located at the extreme N- or C-terminal ends of proteins, although internal locations are not uncommon.

The list of replication proteins that interact with PCNA via a PIP motif is long and growing [23]. Most of the archaeal PIP motif proteins, such as the archaeal DNA-repair enzymes XPF (xeroderma pigmentosum complementation group F) [58] and UDG1 (uracil-DNA glycosylase) [59], or the translesion DNA polymerase Dpo4 [60], lie outside the scope of the present review, but five components of the core replisome have been reported to interact with PCNA via PIP motifs: PolB, PolD, Fen1, RFC-L and DNA ligase (Figure 1). Owing to space limitations, these interactions can be considered only very briefly in the present paper; for a more in-depth treatment of the topic, the interested reader is directed to the primary literature. Particularly relevant are recent studies in which the effects of PIP motif deletion on biochemical function are analysed (see [61,62] for example).

The presence of homo- and hetero-meric archaeal PCNA complexes in different archaea and the abundance of PCNA-interacting proteins in all archaea raises intriguing questions about binding selectivity and how the binding of different partner proteins may be regulated. Where heterotrimeric PCNA complexes are present, it is clear that the different PCNA subunits exhibit preferential binding to different partners. For example, using a combination of Y2H and in vitro pull-down experiments with recombinant proteins, the three subunits of S. solfataricus PCNA have been shown to display unique or highly preferential interactions with DNA ligase, Fen1 and PolB1 [53]. DNA ligase binds preferentially to PCNA3, whereas Fen1 binds to PCNA1 and PolB1 to PCNA2. Thus S. solfataricus PCNA can act as a ‘molecular toolbelt’ with up to three different tools on hand at any one time. How these interactions are regulated remains an open question, however. In addition to binding DNA ligase, PCNA3 also binds preferentially to RFC-L as well as to XPF and UDG1 [53,58,59]. What governs the assembly of particular combinations of partner proteins around PCNA (to form toolbelts tailor-made for specific jobs such as Okazaki fragment processing, replication fork remodelling or DNA repair) is not known.

Future prospects

The results described above represent the first insights into the network of protein–protein interactions that underpin the archaeal chromosomal DNA replication apparatus as it performs its crucial function of high-fidelity duplication of the genetic material (summarized in Figure 1). With the notable exception of the PCNA–PIP interactions summarized briefly in the preceding section, no detailed mapping of interaction surfaces has taken place for any of the interactions identified to date and significant questions remain to be answered about the biological effects on disrupting individual protein–protein interactions on replication efficiency in vivo. Future studies will doubtless address these issues.

In addition, it remains to be seen to what extent the interactions identified to date are regulated by post-translational modification, as is frequently the case in eukaryotic cells. Despite several significant recent advances [63,64], the characterization of post-translational modifications of archaeal proteins is still in its infancy [65] and few attempts have been made to address the in vivo consequences of disrupted modification on protein function. Given the extent to which eukaryotic chromosome replication is regulated by post-translational modification, it seems highly likely that this will play an important role in archaea too. Understanding how post-translational modification regulates protein–protein interaction and replisome function presents a major challenge for the future.

Molecular Biology of Archaea II: A Biochemical Society Focused Meeting held at Robinson College, Cambridge, U.K., 16–18 August 2010. Organized and Edited by Stephen Bell (Oxford, U.K.) and Finn Werner (University College London, U.K.).

Abbreviations

     
  • AAA+

    ATPase associated with various cellular activities

  •  
  • CMG

    Cdc45/MCM/GINS

  •  
  • Fen1

    flap endonuclease 1

  •  
  • MCM

    minichromosome maintenance

  •  
  • NTD

    N-terminal domain

  •  
  • Orc

    origin recognition complex

  •  
  • PCNA

    proliferating-cell nuclear antigen

  •  
  • PIP

    PCNA-interacting protein

  •  
  • PolB

    DNA polymerase B

  •  
  • PolD

    DNA polymerase D

  •  
  • RFC

    replication factor C

  •  
  • RPA

    replication protein A

  •  
  • UDG1

    uracil-DNA glycosylase 1

  •  
  • wH

    winged helix

  •  
  • XPF

    xeroderma pigmentosum complementation group F

  •  
  • Y2H

    yeast two-hybrid

I am grateful to Fiona Gray for her careful reading of the paper and apologize to colleagues whose primary data was not cited owing to space limitations.

Funding

Work in the MacNeill laboratory is currently funded by the Scottish Universities Life Sciences Alliance (SULSA) and by the Wellcome Trust through the Value In People awards programme.

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