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Carcinogenesis Advance Access originally published online on February 20, 2006
Carcinogenesis 2006 27(5):883-892; doi:10.1093/carcin/bgi319
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEW

DNA damage responses and their many interactions with the replication fork

Paul R. Andreassen 1, 2, *, Gary P.H. Ho 3 and Alan D. D'Andrea 3

1 Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center and 2 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA and 3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed at: Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue ML 7013, Cincinnati, OH 45229, USA. Tel: +1 513 636 0499; Email: Paul.Andreassen{at}cchmc.org


   Abstract
Top
 Abstract
Introduction
 Conclusions
 References
 
The cellular response to DNA damage is composed of cell cycle checkpoint and DNA repair mechanisms that serve to ensure proper replication of the genome prior to cell division. The function of the DNA damage response during DNA replication in S-phase is critical to this process. Recent evidence has suggested a number of interrelationships of DNA replication and cellular DNA damage responses. These include S-phase checkpoints which suppress replication initiation or elongation in response to DNA damage. Also, many components of the DNA damage response are required either for the stabilization of, or for restarting, stalled replication forks. Further, translesion synthesis permits DNA replication to proceed in the presence of DNA damage and can be coordinated with subsequent repair by homologous recombination (HR). Finally, cohesion of sister chromatids is established coincident with DNA replication and is required for subsequent DNA repair by homologous recombination. Here we review these processes, all of which occur at, or are related to, the advancing replication fork. We speculate that these multiple interdependencies of DNA replication and DNA damage responses integrate the many steps necessary to ensure accurate duplication of the genome.

Abbreviations: ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3-related; BLM, Bloom syndrome; BRCA1 and 2, BReast CAncer genes/proteins 1 and 2; DSBs, double-strand DNA breaks; FANCD1 and FANCD2, Fanconi anemia proteins D1 and D2; HR, homologous recombination; IR, ionizing radiation; NBS, Nijmegen breakage syndrome; SMC, structural maintenance of chromosomes; TLS, translesion synthesis; UVC, ultraviolet irradiation


   Introduction
Top
 Abstract
 Introduction
Conclusions
 References
 
Fidelity in cell division is requisite for normal development and for the suppression of tumorigenesis (1). One such process in cell division which must be completed with fidelity is DNA replication during S-phase. Cell cycle checkpoints, which delay cell cycle progression until critical steps are completed accurately, cooperate with DNA repair processes to ensure the accurate replication of the genome (1–3). Various mechanisms of DNA repair serve to ensure fidelity in replication by repairing spontaneous or environmentally-induced errors, either before or after the replication of a particular DNA template (4,5).

Many observations have suggested a relationship between normal DNA replication and cellular DNA damage responses. DNA damage, such as that induced by UV radiation or bifunctional crosslinking agents, can induce S-phase arrest (6–8). In such cases, DNA repair is required for the continuation and completion of DNA replication. The interrelationship of DNA replication and DNA repair is also apparent from the involvement of proteins, such as proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), in both processes (9–11). PCNA is an accessory factor for DNA polymerase {delta} (12,13) and RPA is required for the initiation of DNA replication (14).

A further example of the interconnection of S-phase DNA replication and DNA damage responses is evident in the finding that the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) checkpoint kinases, which mediate the responses to double-strand DNA breaks (DSBs) and stalled replication forks, respectively, are involved in regulating the timing of the initiation of replication either in the presence or absence of exogenous DNA damage (15,16). Also, in response to DNA damage, ATM and ATR phosphorylate the minichromosome maintenance (MCM) proteins, which are involved in the initiation of DNA replication (17,18).

Whereas both non-homologous end joining (NHEJ) and homologous recombination (HR) have a role in the repair of DSBs, HR is specifically activated in S-phase, unlike NHEJ (19,20). The recognition of certain types of damage, such as DNA interstrand crosslinks, occurs during S-phase (21). Such observations provide further evidence for the interconnections of DNA replication and cellular responses to DNA damage.

Recent work has yielded mechanistic insight into numerous interactions at the replication fork between S-phase DNA replication and DNA damage responses. Here we will review four such interactions (shown schematically in Figure 1). First, the checkpoint kinases, ATM and ATR, mediate an intra-S checkpoint which suppresses DNA replication in response to different types of DNA damage (22–24). This involves both blocks to replication initiation and the phosphorylation of a multitude of proteins involved in DNA repair (2,25). Second, ATR and the Chk1 kinase, which is activated by ATR (26,27), are required for the response to stalled DNA replication (28–30). This response involves both mechanisms to stabilize the stalled replication fork and mechanisms, including HR, required to restart the stalled replication fork (31–33). Recent results have implicated a number of different DNA repair proteins in this process. Third, recent work has elucidated the role of polymerase switching in translesion synthesis (TLS), which allows continuation of DNA replication by bypassing the lesion (34,35). HR can then cooperate with TLS to mediate the repair of a lesion that stalls the replication fork (34). And fourth, DNA replication generates sister chromatids linked by cohesin proteins. This cohesion is required for subsequent DNA repair by HR (36).


Figure 1
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  		Fig. 1. Overview of important interactions between the DNA replication and DNA damage response processes. When the replication fork encounters a DNA lesion, many components of the cellular response to DNA damage are activated. (A) Checkpoints mediate the suppression of DNA replication when DNA damage is encountered. A key element of this is a block to the initiation of replication origins which would normally be fired subsequently. (B) When a lesion is encountered, checkpoints also stabilize stalled replication forks against collapse by maintaining their association with replicative polymerases. Subsequently, the cell restarts stalled replication forks using HR. (C) Another response to stalled replication is replication bypass of certain lesions. Lesion bypass is mediated by TLS polymerases and can be coupled with subsequent repair by HR. (D) Cohesion of sister chromatids, which is established during DNA replication, is required for efficient repair of DSBs by HR. It is important to note that each of the DNA damage response processes described above occur in proximity to, or are related to, the replication fork.

 
Here, we detail recent insights into how the processes of DNA replication and DNA damage responses cooperate to ensure fidelity in cell division. We suggest that these interrelationships, which occur at the replication fork, serve to coordinate the many processes involved in repairing DNA damage generated both spontaneously and by exogenous sources. The vital importance of this cooperation is illustrated by the many chromosome instability and cancer predisposing diseases, including Bloom syndrome (BLM), ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS) and Fanconi anemia (FA), which represent defects in the cellular response to DNA damage and which thereby result in inaccurate replication of the genome (5,37).

The S-phase checkpoint suppresses DNA replication in response to DNA damage
There are various S-phase checkpoints, including checkpoints which suppress entry into mitosis until DNA replication has been completed (S–M checkpoint) (38) and checkpoints which block DNA replication in S-phase cells in the presence of DNA damage (intra-S-phase checkpoint) (2). Recent progress in understanding the function of the intra-S-phase checkpoint illustrates ways in which DNA synthesis and the DNA damage response interact and will be considered here.

Following the exposure of cells to either ionizing radiation (IR) or ultraviolet irradiation (UVC), both the initiation of DNA replication and the elongation of nascent DNA strands are inhibited (39,40). But quantitatively, inhibition of the initiation of DNA replication is the major component of the intra-S-phase checkpoint (22,39). Inhibition of replication initiation in response to fork progression stalled or blocked by DNA damage, such as UVC, is dependent upon the ATR/MEC1 checkpoint kinase in yeast (41), in Xenopus extracts (15) and in mammalian cells (22). By contrast, inhibition of the initiation of DNA replication following DSBs is independent of the replication fork (2).

Critical steps which regulate the initiation of DNA replication have been elucidated recently. The steps involved in the assembly of the pre-replication complex and in the activation of origin unwinding have been reviewed elsewhere (42). In brief, a pre-replicative complex containing the origin recognition complex (ORC), Cdc6, Cdt1 and six MCM proteins (MCM2–7), is assembled prior to the initiation of replication. Cdc7 and Cdk2 (cyclin dependent kinase 2) act in a sequential manner to load Cdc45 at the origin (43). Binding of Cdc45 and then RPA results in origin unwinding and binding of the primase DNA polymerase {alpha}, which begins replication (44).

A defect in the ability to suppress DNA synthesis following exposure to IR, termed radio-resistant DNA synthesis (RDS), was first described for cells derived from AT patients (39) deficient for the ATM checkpoint kinase (45). Recent work has brought mechanistic insight into how ATM inhibits DNA synthesis following exposure to IR. ATM coordinates two parallel branches of response to IR (25). The first branch directly inhibits the initiation of replication at origins to be fired subsequently. ATM phosphorylates and activates both the Chk1 and Chk2 protein kinases, which in turn phosphorylate the Cdc25A phosphatase at multiple sites (24,46). This leads to Cdc25A degradation (24,47). As a result, the inhibitory phosphorylation of the Cdk2 kinase is maintained (24) and this suppresses the loading of Cdc45 at the origin of replication (25). While it has been reported that AT cells, deficient for ATM, have a partial defect in inhibiting the initiation of DNA synthesis following exposure to UVC (48), ATR and Chk1 have a predominant role in this process (22,49). Nevertheless, similar to IR, exposure to UVC leads to the degradation of Cdc25A and the inhibition of Cdk2 kinase activity (47).

The second branch of IR-induced suppression of DNA synthesis involves ATM-dependent phosphorylation of a number of proteins involved in the DNA damage response, which act to maintain chromosome stability. These include NBS1 (Nijmegen breakage syndrome protein 1), BRCA1 (BReast CAncer protein 1), BRCA2/FANCD1 (BReast CAncer protein 2=Fanconi anemia protein D1) and FANCD2 (Fanconi anemia protein D2). Abrogation of these phosphorylation events results in RDS (50–54). Further, ATM-dependent or ATR-dependent phosphorylation of the cohesin protein, SMC1 (structural maintenance of chromosomes 1), a member of a family of proteins involved in sister chromatid cohesion, is also required to suppress DNA synthesis following exposure to IR (55,56) or UVC (57), respectively. Recently, it has been demonstrated that ATM-dependent phosphorylation of NBS1 and BRCA1 is required for the localization of activated ATM to sites of DSBs (58). The phosphorylation of NBS1 and BRCA1 are interdependent and result in the downstream phosphorylation of SMC1 (58). While it is unknown how phosphorylated SMC1 affects the intra-S-phase IR checkpoint, it has been determined that it is not through inhibition of Cdc45 loading at the origin (25).

It has recently been reported that deletion of the fission yeast homolog of NBS1 results in RDS (59). Interestingly, these authors propose a model in which NBS1 does not directly inhibit DNA synthesis following DNA damage but instead mediates recombination-dependent repair that slows DNA synthesis. This appears to be consistent with the finding that NBS1 does not regulate Cdc45 loading, and by extension origin firing, following DNA damage in mammalian cells (25). It is important to note that ATM, NBS1 and BRCA1 have all been implicated in HR in vertebrate cells (60–62) and that recent experimental evidence suggests the slowing of the replication fork by HR in mammalian cells (63). While evidence exists for interactions of NBS1 (64) and BRCA1 (65) with FANCD2, the functional relationship of FANCD2, or of BRCA2/FANCD1, to the ATM–NBS1–BRCA1–SMC1 branch of this S-phase checkpoint has not been determined. A model for the cooperation of the two branches of the intra-S-phase checkpoint affected by ATM in response to IR is shown in Figure 2.


Figure 2
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  		Fig. 2. The ATM checkpoint kinase coordinates a two-branched response to IR that suppresses DNA replication. In one branch (left), phosphorylation of Chk2 (and Chk1) kinase activates the phosphorylation of the Cdc25A phosphatase thereby targeting it for degradation. This maintains inhibitory phosphorylation of the Cdk2 kinase and prevents the loading of Cdc45, resulting in the suppression of the initiation of DNA synthesis. The second branch (right) does not inhibit the loading of Cdc45, but does lead to the recruitment of SMC1 in a phospho-NBS1- and phospho-BRCA1-dependent manner. We propose that HR-dependent repair, mediated by a protein complex including SMC1, NBS1 and BRCA1, blocks the advance of the replication fork.

 
Repair-dependent slowing of the replication fork appears to be consistent with old reports suggesting that in mammalian cells either IR or UVC slow elongation of nascent DNA strands at sites where DNA synthesis had already been initiated (39,40). Importantly, cells from Xeroderma Pigmentosum (XPV) patients, which are deficient for the repair of DNA damage induced by UVC, display an excessive slowing of elongation following exposure to UVC (40). In this case, defective DNA repair results in increased DNA damage and this further slows the replication fork.

Role of the DNA damage response in restarting/stabilizing stalled replication forks
The DNA replication and DNA damage response processes also cooperate in protecting the cell against stalled replication (recently reviewed (31,32)). This was first characterized extensively in bacteria, but more recently similar mechanisms have been found to function in yeast and vertebrate cells. Replication can stall due to double-strand or single-strand DNA breaks that arise during DNA synthesis, due to adducts resulting from reactive oxygen species (ROS) in the cell, or due to adverse secondary structures present in DNA (31,66,67). Failure to stabilize stalled replication forks can result in their collapse and ultimately in genetic instability (66–70).

Mechanisms which stabilize stalled replication forks result in the continued association of DNA polymerase complexes with nascent DNA strands (71). This is important, since it permits efficient resumption of DNA synthesis once it has restarted. Recovery of stalled replication forks involves HR and will be discussed below. Two elements of the DNA damage response: checkpoint kinases, including Chk1 and MEC1/ATR, and RecQ family helicases are central to both stabilization and recovery of stalled replication forks. These components have functions which are conserved from yeast to mammals. The roles of checkpoint kinases (72) and RecQ helicases (4) in the cellular response to stalled replication have been reviewed recently.

While both checkpoints (41,68,71,73) and RecQ helicases (71,74) have a role in preventing the collapse of stalled replication forks, other proteins have also been identified which play a role in this process. This includes BRCA2 (75), which has an important role in HR (76). It is interesting that, by its role in HR, BRCA2 may also have an important role in restarting stalled replication forks.

Potential roles and mechanisms for HR in restarting stalled replication have been recently reviewed by Helleday (33). Increasingly, components involved in the processing of stalled replication forks are being identified and their relationship to HR determined. Fission yeast and budding yeast RecQ helicases, Rqh1 and Sgs1, respectively (74,77) and BLM (78), a mammalian RecQ homolog, are required to restart stalled replication forks. Importantly, these RecQ helicases regulate the formation of Holliday junction recombination intermediates (79,80). RecQ helicase-dependent regression of stalled replication forks can lead to the formation of Holliday junctions, which have been visualized in yeast (81). The Mus1-Eme1 endonuclease resolves Holliday junctions in vitro (82) and is required for the processing of stalled replication forks (83). It has been proposed that an increased frequency or complexity of lesions at stalled replication forks leads to HR involving RAD51-dependent strand invasion (84). The RecQ helicases may suppress RAD51-dependent strand invasion and favor restarting the stalled replication fork by fork regression and subsequent resolution by the Mus1-Eme1 resolvase (84). Accordingly, a deficiency for Rqh1, Sgs1 or BLM results in an increased frequency of HR (77,84,85). Further evidence for a role of HR in restarting stalled replication forks comes from the finding that Rad51 foci and HR are stimulated by stalled replication (86–88). Additionally, Poly(ADP-ribose) polymerase-1 (PARP-1) is required in an unknown manner to restart stalled replication (89).

Recent work has provided insight into steps involved in the recruitment of machinery involved in the stabilization and/or reactivation of stalled replication forks in mammalian cells. The single-strand DNA binding complex, RPA, is required for the recruitment of ATR at sites of stalled replication (90) and appears to regulate the Rad51 recombinase (91–93). Importantly, BLM is recruited to the stalled replication fork in mammalian cells in a process that requires the checkpoint mediator 53BP1 (28). The recruitment of both 53BP1 and BLM is regulated by the Chk1 kinase, which is activated by ATR (26,27). It has also been reported that ATR phosphorylates BLM directly (78). Additionally, BLM is required for the recruitment of p53, which then presumably regulates RAD51 and HR (84). Another element, BRCA1, is phosphorylated by and colocalizes with, ATR in response to stalled replication (30). The relationship of BRCA1 and BLM recruitment is unknown. While the formation and colocalization of phosphorylated histone H2AX, 53BP1 and BRCA1 foci occurs in response to stalled replication (94), recruitment of 53BP1 and BLM to stalled replication forks does not require H2AX (28). A model for the recruitment of DNA damage response proteins to the stalled replication fork is shown in Figure 3.


Figure 3
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  		Fig. 3. Model for the recruitment of proteins involved in stabilizing or restarting the stalled replication fork. The single-strand DNA binding complex, RPA, is recruited to exposed single-strand DNA. This leads to the recruitment of the Rad51 recombinase and to the recruitment and activation of ATR. ATR then phosphorylates BRCA1, enabling BRCA1 recruitment and also phosphorylates the BLM helicase. Importantly, ATR phosphorylates and activates Chk1. Chk1 is required for the 53BP1-dependent recruitment of BLM. Once in place BLM recruits p53, which may regulate Rad51-dependent HR involved in restarting the stalled replication fork. BLM is required to stabilize and restart stalled replication forks.

 
TLS (bypass) allows S-phase DNA replication to proceed prior to repair of the lesion by HR
Another response to DNA damage that stalls DNA replication is replication bypass, also known as TLS. The process of TLS is an interesting example of the interactions of replicative DNA synthesis and DNA damage responses. TLS utilizes lower fidelity Y family DNA polymerases, including pol eta ({eta}), iota ({iota}), kappa ({kappa}), REV1 and the B family polymerases REV3/7 ({zeta}) (recently reviewed in refs 35 and 95). These polymerases function specifically in the replication of damaged, but not undamaged, DNA. This allows replication of lesions that would otherwise block DNA replication.

DNA repair processes, such as base excision repair (BER) and nucleotide excision repair (NER), remove most of the DNA damage present in the cell. But damage which escapes repair by these processes can stall replication, lead to fork collapse, and ultimately result in genetic instability (34,91). Work more than three decades ago demonstrated that mammalian cells are capable of synthesizing intact daughter strands of DNA in the presence of persistent DNA damage on the parental strand (96). Recent work has led to the identification and characterization of translesion polymerases involved in this process (35,95).

While the relative importance of TLS and HR in responding to replication blocking lesions in mammalian cells is unknown, both processes cooperate to prevent replication fork collapse in the chicken B-cell line, DT40 (97,98). Interestingly, recent work with DT40 cells has indicated a potential role for TLS in HR itself (98–100). Importantly, unhooked repair intermediates for DNA interstrand crosslinks induce replication stalling and DSBs. Gap filling by TLS stabilizes the lesion prior to subsequent repair by mechanisms such as NER and HR (99).

Homologs involved in TLS, as well as HR, are conserved from bacteria to humans (34,101). Because of the lower fidelity of Y family polymerases (35,95), it is critically important that their use is restricted to replicating lesions that have not been repaired by other means and which will thereby stall DNA replication. This is accomplished by polymerase switching. Important steps in polymerase switching have recently been elucidated (101). The target of regulation is PCNA, the processivity factor for DNA polymerase {delta} in leading strand DNA synthesis (12,102). Monoubiquitination of PCNA in yeast and humans requires the RAD6/RAD18 ubiquitination machinery (103,104) and is essential for TLS (104,105). PCNA associates both with pol {delta} and with the Y family polymerases {eta}, {iota} and {kappa} (104,106–108). A switch to a Y family polymerase, when pol {delta} (or pol {varepsilon}) encounters a blocking lesion, allows DNA replication across the lesion. Because Y family polymerases copy undamaged DNA with lower processivity than damaged DNA, this allows a switch back to pol {delta} or {varepsilon} following lesion bypass (109). Coupled with the 3'-5' exonuclease activity of pol {delta} and {varepsilon}, this can result in error-free bypass depending on the DNA lesion (95,110,111). Whether monoubiquitination favors the dissociation of pol {delta} with the primer terminus, favors association of TLS polymerases with the primer terminus, or both, is unknown (101). It is clear though, that the association of PCNA with sites of DNA damage is regulated through its monoubiquitination (112). The interaction between processive DNA replication and the DNA damage response in polymerase switching is summarized in Figure 4.


Figure 4
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  		Fig. 4. Monoubiquitination of PCNA mediates polymerase switching when the replication fork encounters DNA damage. Normal replicative DNA synthesis is carried out by DNA pol {delta}, in association with the processivity factor, PCNA. When DNA damage is encountered, PCNA is monoubiquitinated by Rad6/Rad18. This allows a switch to TLS polymerases, such as pol {eta} and pol {kappa}, which then, in association with PCNA, synthesize across the lesion.

 
A variant of XPV, which is associated with sunlight-induced cancers and a defect in the replication of DNA containing UV dimers, represents a mutation in the translesion polymerase {eta} (113). UV dimers represent one type of replication blocking lesion which can be bypassed by translesion polymerases. The cancer predisposition associated with mutation of polymerase {eta} illustrates the critical importance of the function of translesion polymerases in response to DNA damage encountered by the replication fork.

Role of cohesion in DNA repair
Cohesion of sister chromatids is mediated by a family of proteins called cohesins (114,115). The establishment of cohesion is coupled to the DNA replication machinery (reviewed in (114,116)) and cohesion is integral to the DNA damage response. As discussed above, ATM-dependent phosphorylation of the cohesin protein SMC1 is required for the intra-S checkpoint following exposure to IR (55,56,58). In addition, it is becoming apparent that cohesins have an important role in HR.

In a mitotic cell cycle, cohesin is composed of a tetrameric complex of Scc1, Scc3 and two SMC (structural maintenance of chromosomes) members, SMC1 and SMC3 (117–119). Loading of cohesins onto chromatin is dependent on a non-core subunit, Scc2, both in yeast and in frog extracts (117,120–122). While the specific timing of cohesin loading differs between yeast and either Xenopus extracts or mammalian cells, recent work suggests that Scc2 recruits cohesin to the pre-replication complex which regulates the initiation of replication (121–123). At least in Xenopus extracts, however, cohesin loading does not require initiation of DNA replication.

Once loaded cohesins are in place, cohesion is established as the nascent sister chromatid is generated during DNA replication. There are a number of interactions between the replication machinery and elements involved in establishing cohesion (recently reviewed in refs 114 and 116). Among these, Ctf7/Eco1, a non-cohesin subunit required to establish cohesion, interacts genetically with PCNA (117,124). And the replicative polymerase, pol{varepsilon}, associates with SMC1 and Ctf7/Eco1 (125). Presumably this interaction between polymerases and cohesin components is established after the initiation of replication. Alternative replication factor C (RFC) complexes which are required for sister chromatid cohesion have been reported (126,127). Ctf7/Eco1 binds to RFC and alternative RFC complexes (128). In this way, RFC complexes, which load either PCNA or the Rad9-Rad1-Hus1 checkpoint complex onto chromatin, potentially link cohesion to DNA replication and checkpoint signaling (116,128). Importantly, a human homolog of yeast EcoI, Esco2, is mutated in Roberts syndrome (129). Mutation of EcoI in yeast (130) or Esco2 (131) in humans is associated with sensitivity to DNA damaging agents, demonstrating another linkage between the establishment of cohesion in S-phase and subsequent function of DNA damage responses. In this context, it is interesting that a yeast screen for non-cohesin components involved in cohesion identified genes involved in the DNA damage response. This includes Sgs1, which is involved in the response to stalled replication as discussed earlier and genes involved in DNA repair (132).

The finding that cohesin can relocalize to sites of DNA damage suggests a more direct role for cohesins in the DNA damage response (133). Indeed, cohesins play a specific role in the repair of DSBs by HR. Cohesion of sister chromatids, which are the preferred template for HR, is required for efficient repair of DSBs by HR (36). Further, Rad21, which is required for the repair of DSBs induced by IR in fission yeast, is the cohesin Scc1 (36,134,135). Interestingly, in yeast, RAD50, which is part of the MRE11–RAD50–NBS1 complex, appears to function in a pathway with rad21/Scc1 to promote the utilization of the sister chromatid to repair DSBs by HR (136). Additionally, in mammalian cells SMC1 is a component of the RC-1 recombination complex (137). It has recently been reported that cohesin can also be recruited to sites of DSBs in budding yeast during G2, independent of the replication fork (138). Thus, cohesion established during DNA replication may have a specific function in DNA repair during S-phase. The coordination of replication-coupled cohesion with DSB repair is summarized in Figure 5.


Figure 5
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  		Fig. 5. HR-dependent repair of DSBs is mediated by cohesion established during DNA replication. We propose that a tetrameric cohesin complex that is associated with the pre-replication complex (pre-RC) via Scc2 establishes cohesion between sister chromatids as the replication machinery advances the replication fork. The cohesin complex then cooperates with RAD50, which is in a complex with MRE11 and NBS1, to mediate HR-dependent repair of DSBs using the paired sister chromatid.

 
It has recently been determined that degradation of the cohesin Scc1 is required both for anaphase separation of chromosomes and for interphase DNA repair (139). Thus, the release of sister chromatid cohesion may also be an important step in repair.


   Conclusions
Top
 Abstract
 Introduction
 Conclusions
References
 
Cellular DNA damage responses, which are composed of cell cycle checkpoints and DNA repair mechanisms, and S-phase DNA replication are highly interrelated and interdependent. Recent work has added to our understanding of the mechanistic basis of these interrelationships. Strikingly, S-phase DNA replication and DNA damage responses are related in a number of processes, including S-phase checkpoints, the cellular response to stalled replication forks, translesion synthesis to bypass unrepaired DNA lesions, and sister chromatid cohesion. We suggest that this allows the coordination of the many steps involved in faithfully replicating DNA. For example, the checkpoint mechanisms which sense and signal the cellular response to DNA damage are also centrally important for stabilizing and processing the stalled replication fork. Thus, the cell utilizes the same signaling mechanisms to attempt to prevent stalling of replication forks, to avoid their collapse, and ultimately, if necessary, to restart the stalled replication fork. Another example of the coordination of the steps required for faithful replication of DNA is the potential for the combined action of HR and lesion bypass by TLS. In this way, the cell is capable of responding to a broader range of lesions which can stall replication.

It is important to point out that the various processes involved in assuring accurate DNA replication may be occurring simultaneously. For example, cohesion is established as sister chromatids are generated by DNA synthesis. A template for DNA repair by HR is therefore potentially generated as lesions arise during DNA synthesis. As another example, reversion of stalled replication forks can allow the generation of a Holliday junction required to restart stalled replication. Given the potentially close temporal proximity of events required for faithful DNA replication during S-phase, it may not be surprising that these processes are integrated together. We suggest that it is this integration, which is achieved by coordination of S-phase DNA synthesis and the DNA damage response, which allows the replication of the genome with the highest possible fidelity.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Conclusions
 References
 

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Received July 28, 2005; revised September 5, 2005; accepted December 17, 2005.


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