Human Molecular Genetics, 2002, Vol. 11, No. 20 2447-2453
© 2002 Oxford University Press
Protecting genomic integrity during DNA replication: correlation between Werner's and Bloom's syndrome gene products and the MRE11 complex
CNRS–UPR2169 Instabilité Génétique et Cancer, Institut de Recherches sur le Cancer André Lwoff, 7 Rue Guy Moquet, BP 8, 94801 Villejuif, France
Received July 8, 2002; Accepted July 15, 2002
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ABSTRACT |
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 TOP ABSTRACT WERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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DNA replication is a critical step for cells because of the propensity of replication forks to stall, as a consequence either of endogenous DNA damage or of the propensity of repeated sequences to form tertiary structures, which can impede fork progression. Moreover, as a result of stalled replication fork processing, potentially lethal and recombinogenic double-strand breaks can be formed. Thus cells (in particular human cells) have evolved a sophisticated network to deal with replication fork stall. Recently, WRN and BLM, two helicases mutated in the genetic hereditary conditions Werner and Bloom syndromes, appeared crucial for the correct recovery from replication arrest; however, it seems that other proteins assist them in this role. One of the possible partners is the MRE11 complex, which is found mutated in two other genetic instability syndromes: Nijmegen breakage syndrome and ataxia telangiectasia-like disorder. This strongly supports the idea of a central role of preventing crisis during DNA replication for the maintenance of genomic stability and integrity in human cells.
Correct completion of DNA replication is of crucial importance for the fidelity with which genetic information is passed from a parent cell to daughter cells, as well as for cellular viability. Incomplete or incorrect replication of a damaged template can give rise to gross chromosomal instability, accumulation of deleterious mutations and, in multicellular organisms, to genetic diseases and/or cancer (1,2). Several types of exogenous sources of DNA damage can interfere with DNA replication, and, furthermore, DNA replication can stall as a consequence of replication across particular DNA structures such as inverted repeats, palindromic sequences and trinucleotide repeat tracts that show a propensity to form hairpin structures, which block replication and are highly recombinogenic (3–6). Replication fork stall can give rise to DNA double-strand break (DSB) formation by itself or as a consequence of the active processing of the stalled replication forks (7–9). DSBs are a significant threat to cells because their misrepair directly generates chromosomal rearrangements and cancer (10,11). Thus, it is not surprising that mammalian cells have evolved a complex surveillance network comprising DNA repair, DNA replication and checkpoint genes to maintain genome stability during S phase (12,13). The importance of this network is also underscored by the observation that mutations in such genes often result in genetic diseases characterized by wide genomic instability and cancer predisposition (1,14,15).
In recent years, it has been recognized that the genes encoding two RecQ-class DNA helicases (WRN and BLM) and those encoding the three components of the MRE11 complex (MRE11, RAD50 and NBS1) are of particular significance for the maintenance of genomic integrity and cellular viability during DNA replication. (16,17). In this review, we shall focus on the roles of WRN, BLM and the MRE11 complex in preventing genomic instability during DNA replication, paying particular attention to their relationships.
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WERNER AND BLOOM SYNDROMES |
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TOPABSTRACTWERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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Werner syndrome (WS) is an autosomal recessive disorder manifested by premature onset of age-related phenotypes, including cancer (18,19). Bloom syndrome (BS) is another rare genetic disease characterized by predisposition to a wide variety of cancers (20,21). One of the major hallmarks shared by these two syndromes is a wide genomic instability (Table 1). In WS cells, this instability appears as spontaneous chromosomal abnormalities: chromosome breaks, complex rearrangements and deletions (22–28). A striking characteristic of WS cells is so-called ‘variegated translocation mosaicism’, which involves the expansion of different structural chromosome rearrangements in different clones from the same cell line (29). Another sign of genomic instability is abnormal fluctuation of telomere length (30). Along with spontaneous genomic instability, cells from WS individuals show a delayed S phase (22,31) and a hypersensitivity to agents that interfere with DNA replication (32–34). In addition, WRN has been found to physically interact and/or co-localize with several proteins involved in DNA replication or control of genetic stability during S phase (35–38) (Table 2). In BS cells, genomic instability is manifested as a 10-fold higher frequency of reciprocal exchanges between either sister chromatid (SCE) or homologous chromosomes (20,39). Also, BS cells show S-phase defects (40), and BLM has recently been associated with other proteins involved in S-phase surveillance (41–45) (Table 2).
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WRN has been mapped at 8p11–12, and BLM at 15q26.1 (46–49). The gene products of WRN and BLM are two large RecQ helicases (47,50) that share
41% homology, which is greater in the central DEAH helicase domain and in the additional HRDC domains (Helicase and RNase DC-terminal) (51), but also present important distinctive features. The Werner syndrome helicase (WRN) has a unique N-terminal domain with exonuclease activity (52–54), whereas the Bloom syndrome protein (BLM) has at its N-terminus a region with no significant homology to any of the known proteins (14). All WS mutations (nonsense, frameshift and deletion/insertion) give raise to truncated proteins lacking the C-terminal nuclear localization signal, suggesting that absence of correct localization of WRN is causative for the syndrome. No missense mutations have been reported in WS up to now. On the other hand, all kind of mutations have been associated with BS, including missense mutations occurring in the DEAH domain and leading to reduced helicase activity. The two helicases WRN and BLM present the same directionality, 5'–3', as well as a considerable overlap in their preferred substrates, at least in vitro (55). Of particular significance, they can unwind G-tetraplex or 4-way structures as well as other ‘abnormal’ DNA structures, such as hairpins, which are normally formed during replication of complex genomes (36,56–64) (Table 2). However, the physiological substrates of WRN and BLM in vivo and their relevance for the pathology still wait to be revealed. |
SYNDROMES ASSOCIATED WITH MUTATIONS IN THE MRE11 COMPLEX |
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TOPABSTRACTWERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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The genes that encode for the components of the MRE11 complex were first identified in yeast. The yeast Mre11 complex is formed by three proteins—Rad50, Mre11 and Xrs2—and is a key participant in DNA repair, telomere maintenance and meiosis (65). The mammalian MRE11 complex also appears to be composed of three subunits—RAD50, MRE11 and NBS1 (which replaces Xrs2) (66–69).
NBS1 was the first component of the complex to be associated with a genetic disease, NBS1 being found mutated in the genetic disease Nijmegen breakage syndrome (NBS) (70). NBS is characterized by developmental defects, immune deficiency and a high incidence of cancer (71). NBS cells present genomic instability in the form of chromosome breakage and fail to arrest DNA synthesis following DNA damage (72) (Table 1). Furthermore, NBS cells are sensitive to DNA-damaging agents causing replication fork stall (73). In a similar manner, it was found that mutations in the MRE11 gene determine another genetic disease, the ataxia-telangiectasia-like disorder (A-TLD), which is phenotypically similar to NBS and to another genetic disease, ataxia telangiectasia (A-T) (74). Similarly to NBS cells, A-TLD cell lines present chromosome instability, inability to properly arrest DNA replication after DNA damage, and hypersensitivity to DNA damage induced by ionizing radiation (72) (Table 1). Strikingly, all of the mutations found in NBS and A-TLD are hypomorphic, which is consistent with the embryonically lethal phenotype of mice knocked-out for the components of the MRE11 complex (75–77). To date, no mutations in RAD50 have been associated with genetic diseases.
The MRE11 protein shows either 3'–5' DNA exonuclease activity or DNA endonuclease activity, which can be differently modulated by binding to RAD50 and NBS1 (78–81) (Table 2). RAD50 belongs to the ‘structural maintenance of chromosomes’ (SMC) family of proteins (82), and seems to adopt a homodimeric structure that is thought to serve as a molecular pin to bring together two MRE11 molecules (83). On the other hand, NBS1 contains at its N terminus two globular domains that are involved in protein–protein interaction—the forkhead-associated (FHA) and BRCT (BRCA1 C-terminal) domains—whereas at its C-terminus is located the region responsible for binding to MRE11 (17). The function of NBS1 has been linked to the checkpoint signalling cascade (84).
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FUNCTIONS OF WRN, BLM AND THE MRE11 COMPLEX IN MANTAINING GENOMIC STABILITY DURING DNA REPLICATION |
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TOPABSTRACTWERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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As stated above, preventing DNA damage and mutations during DNA replication is of crucial importance for the cell. In fact, several kinds of DNA damage, as well as endogenous DNA structures, can interfere with DNA duplication, leading to replication fork stall. Stalling of the replication fork requires systems that prevent its collapse and dissociation or mechanisms resulting in replication re-start near the site of stalling (2). Mechanisms of replication re-start after stalling are better known in bacteria and lower eukaryotes, but there is growing evidence that they are conserved in humans. Stalling of the replication machinery can require a reaction called ‘reversal fork reaction’ (RFR) to re-originate an active replication fork, or, alternatively, it is necessary to pass through the formation of DSB and recombination in order to complete replication (7–9,85). This situation occurs because near or at the stalled replication fork, abnormal DNA structures are generally formed—sometimes cruciform structures close to Holliday junctions (60). Such structures have to be recognized and resolved. In bacteria, resolution of stalled replication forks involves the RecQ helicase and in yeast the RecQ-like helicases Sgs1 (Saccharomyces cerevisiae) and Rqh1 (Schizosaccharomyces pombe) (86,87). Thus, it is not surprising that WRN and BLM are good candidates for carrying out the RFR in humans, being capable of binding and resolving these structures in vitro. Moreover, a role for WRN and BLM in recovery from replicative blockage is supported by the sensitivity of WS and BS cells to hydroxyurea (88,89), which causes replication arrest by depleting the dNTP pool—a sensitivity that is also found in the Sgs1 and Rqh1 yeast mutants (90,91).
However, recent data have indicated a more complicated and intriguing scenario, reconciling the duality between WRN and BLM, as well as the role of the MRE11 complex during DNA replication. A possible model of the cooperative function of WRN, BLM and the MRE11 complex in the resolution of the stalled replication fork is proposed in Figure 1.
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Much evidence has demonstrated that the MRE11 complex actually has an important role not only in DSB repair as a consequence of exogenous DNA damage, but also in the prevention of DSB formation during the normal replicative process, and possibly in its repair (92–94). Moreover, MRE11-null cells present gross chromosomal rearrangements and a terminal apoptotic phenotype, which could be the result of unprotected DNA synthesis (75,95). In addition, cells containing an inactive MRE11 complex are sensitive to mitomycin C (73,96), an agent that ultimately provokes replication fork stall.
It has been demonstrated that relocalization of the MRE11 complex after replication arrest is absent when BLM is lacking and that BLM and MRE11 can co-localize in the nucleus and interact physically with each other (41,88). The kinetics of the relocalization of BLM and MRE11 after replication arrest is rapid and is close to that of complete inhibition of DNA synthesis, suggest that BLB and MRE11 perform an earlier role in sensing and binding structures that cause replication fork arrest or that form as a consequence of it (41,88). Indeed, BLM binds many different structures that can be found at the stalled replication fork, and it is possible that it is required to resolve these structures before the MRE11 complex. It is interesting that BLM becomes phosphorylated in an ATR-dependent manner after replication blockage and that phosphorylation is required for correct assembly of the MRE11 complex at the stalled fork (88,97). The BLM/MRE11 complex association, at this stage, could function as the RecBCD complex does in bacteria (98), allowing resolution of the abnormal structures and restoring an active replication fork. From this point of view, the MRE11 complex could provide BLM with the exo- and endonuclease functions essential to complete resolution, as well as repairing DSB formed during resolution. Interestingly, it has recently been reported that MRE11 shows activity towards hairpin structures such as those that can be formed during replication of DNA palindromes (99). It is possible that the absence of BLM, and the consequently impaired relocalization of the MRE11 complex, force the cells to use alternative pathways to overcome replication fork arrest during the normal DNA replicative process. BS cells present a hyper-recombinational phenotype and elevated RAD51 relocalization (14,100–103), which is a marker of recombinational repair. Accordingly, the elevated yield of SCEs may actually derive from the enforced use of recombination to resolve arrested replication forks. In fact, it has been shown that SCE formation is a recombination-dependent event (104).
BLM-mediated recruitment of the MRE11 complex could also contribute to transduction of a checkpoint signal to the cell cycle machinery through NBS1 phosphorylation, even if it seems that other pathways can signal the requirement to stop DNA synthesis, since a limited defect in S-phase checkpoint response is found in BS cells after replication fork arrest (88,97). It is also possible that NBS1 phosphorylation serves to reinforce S-phase arrest, for instance when more time is required to handle the arrested replication fork (92). On the other hand, the MRE11 complex is normally relocalized in the absence of an active WRN helicase (88), even if WRN is phosphorylated in an ATR-dependent manner and relocalizes after replication arrest as BLM does (P. Pichierri et al., submitted for publication). How does one reconcile the apparently similar substrate preference between WRN and BLM, the observed similar sensitivity to agents inducing replication arrest and the completely different phenotype regarding functionality of the MRE11 complex? One possibility is that BLM and WRN do not perform overlapping roles, perhaps acting at different moments of the response to replication fork stall. One possibility, according to the kinetics of relocalization of WRN and BLM at the stalled fork and to the time-course of recruitment of the MRE11 complex (88 and our unpublished observations), is that WRN is recruited at the sites of arrested fork to assist the activity of MRE11 in handling specific DNA structures and/or complete replication recovery via recombination. In any case, recent data are emerging indicating mutually exclusive roles for these two helicases (105,106). Furthermore, the absence of WRN seems to affect later steps in the resolution of a stalled replication fork—possibly those involving recombinationally mediated restart of replication. Hence, in WS, replication arrest causes apoptosis in cells engaged in recombination (89). Consistently, WRN has been co-localized with RAD51 (107). Thus, it is likely that WRN acts after BLM/MRE11 complex or functions in an alternative pathway of stalled replication fork recovery. BLM can also perform additional roles at the later stages of recovery of the stalled replication fork, since it is able to co-localize and interact physically with RAD51 (103).
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CONCLUSIONS |
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TOPABSTRACTWERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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Genetic and biochemical analyses have indicated that WRN, BLM and the MRE11 complex can function in pathways ensuing genomic stability during DNA replication, from stalled replication fork recovery to checkpoint. The discovery of a functional link between the RecQ helicases WRN and BLM and the MRE11 complex is encouraging, because it will allow better comprehension of the mechanisms that control proper completion of DNA replication in humans. Further studies will be necessary in order to clarify the relationships among these proteins and between them and the S-phase checkpoint signalling cascade. Because of rapid progress in the study of the functions of the two RecQ homologues and of the MRE11 complex, we shall soon obtain a more precise scenario concerning how these proteins contribute to preserving genomic integrity during S phase.
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ACKNOWLEDGEMENTS |
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Work in the authors' laboratory was partially supported by grants from Università della Tuscia/MIUR (Ministero Italiano Università e Ricerca), by Fondazione CaRiVit and by EDF (Electricitè de France).
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +33 149583409; Fax: +33 149583411; Email: pichier{at}vjf.cnrs.fr
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TOPABSTRACTWERNER AND BLOOM SYNDROMESSYNDROMES ASSOCIATED WITH...FUNCTIONS OF WRN, BLM...CONCLUSIONSREFERENCES |
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