A model for replication repair in mammalian cells

Higgins, N. Patrick; Kato, Karen; Strauss, Bernard S.

doi:10.1016/0022-2836(76)90156-x

Cited by 422 publications

(285 citation statements)

References 20 publications

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“…Because the RAD6͞RAD18 pathway does not repair double-strand breaks (30), the recombination mechanism responsible for its error-free damage tolerance component presumably operates on intact stalled forks rather than those that have generated these breaks. The model proposed by Higgins and coworkers (25), modified to include lesions on both DNA strands as in the present case, appears to be a plausible candidate for such a process (Fig. 2).…”

Section: Discussionmentioning

confidence: 60%

“…Moreover, if as suggested in ref. 24, the mechanism depends on transient template strand switching of the kind proposed by Higgins and coworkers (25), which entails recombination by informational exchange between partially replicated sister strands, an additional difficulty is the inability of monitoring such an event by conventional genetic methods. We have therefore investigated the mechanism by transforming an isogenic series of excision defective yeast strains with plasmid constructs that carry a single thymine-thymine pyrimidine (6-4) pyrimidinone photoadduct in each strand at staggered positions 28 base pairs (bp) apart.…”

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confidence: 99%

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The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination

Zhang

Lawrence

2005

Proc. Natl. Acad. Sci. U.S.A.

176

167

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Evidence for an error-free DNA damage tolerance process in eukaryotes (also called postreplication repair) has existed for more than two decades, but its underlying mechanism, although known to be different from that in prokaryotes, has remained elusive. We have investigated this mechanism in Saccharomyces cerevisiae, in which it is the major component of the RAD6͞RAD18 pathway, by transforming an isogenic set of rad1⌬ excision-defective strains with plasmids that carry a single thymine-thymine pyrimidine (6-4) pyrimidinone photoadduct in each strand at staggered positions 28 base pairs apart. C-C mismatches placed opposite each of the T-T photoproducts permit unambiguous detection of the events that can lead to the completion of replication: sister-strand recombination or translesion replication on one or the other strand. Despite the severe block to replication that these lesions impose, we find that more than half of the plasmids were fully replicated in a rad1⌬ strain and that >90% of them achieved this end by recombination between partially replicated sister strands within the interlesion region. Approximately 60 -70% of these events depended on the error-free component of the RAD6͞RAD18 pathway, with the remaining events depended on RAD52; these two processes account for almost all of the recombination, which depended neither on DNA polymerase nor on mismatch repair. We conclude that the error-free component of the RAD6͞RAD18 pathway completes replication by a mechanism employing recombination between partially replicated sister strands, possibly by means of transient template strand switching or copy choice.postreplication repair ͉ Saccharomyces cerevisiae D NA damage tolerance processes, also called postreplication repair, are a major part of the repertoire of mechanisms used by organisms to counter the continuous onslaught of genomic damage. Unlike mechanisms that repair the damage, however, damage tolerance processes are concerned with overcoming one of its serious consequences, namely, the ability of such damage to block the progress of the DNA replicases. At least two processes are used to achieve this end: translesion replication, in which specialized DNA polymerases replicate past lesions, often generating mutations but accounting for only a minor fraction of the damage tolerance, and an error-free process that accounts for the major fraction. The existence of the latter process has been known for Ͼ30 years from studies in excision repair-deficient strains of the molecular size of DNA synthesized at various times after UV irradiation; although DNA synthesized soon after irradiation is of smaller size than its counterpart from unirradiated cells, indicating the presence of gaps and interruptions, its size corresponds to that of control DNA when isolated from the irradiated cells after a period of incubation, showing that the gaps have been filled and interruptions sealed (1). Although initially discovered in Escherichia coli (1), similar results have also been found in other organisms, including mam...

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination

Zhang

Lawrence

2005

Proc. Natl. Acad. Sci. U.S.A.

176

167

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“…It is thus unlikely that FANCM promotes branch migration of Holliday junctions during recombinational repair of double-strand breaks. On the other hand, four-way junctions not only emerge from an exchange of strands between homologous duplexes, but can also arise from the regression of stalled replication forks (22). Because FANCM binds equally well to model replication forks as to Holliday junctions (19) and FA proteins are associated with the response to replication stress, a more likely possibility is that FANCM remodels the branch point of stalled replication forks.…”

mentioning

confidence: 99%

Remodeling of DNA replication structures by the branch point translocase FANCM

Gari

Décaillet²,

Delannoy³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

209

178

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Fanconi anemia (FA) is a genetically heterogeneous chromosome instability syndrome associated with congenital abnormalities, bone marrow failure, and cancer predisposition. Eight FA proteins form a nuclear core complex, which promotes tolerance of DNA lesions in S phase, but the underlying mechanisms are still elusive. We reported recently that the FA core complex protein FANCM can translocate Holliday junctions. Here we show that FANCM promotes reversal of model replication forks via concerted displacement and annealing of the nascent and parental DNA strands. Fork reversal by FANCM also occurs when the lagging strand template is partially single-stranded and bound by RPA. The combined fork reversal and branch migration activities of FANCM lead to extensive regression of model replication forks. These observations provide evidence that FANCM can remodel replication fork structures and suggest a mechanism by which FANCM could promote DNA damage tolerance in S phase.fanconi anemia ͉ replication fork A variety of structural and chemical alterations in DNA can hinder the progression of replication forks and precipitate the formation of gross chromosomal rearrangements. These hurdles impose distinct structural constraints in the template DNA, which elicit the action of diverse lesion bypass or lesion tolerance pathways (1, 2). Covalent links between complementary DNA strands constitute a unique challenge to replicating cells, because they preclude strand separation and, hence, completely block fork progression. In mammalian cells, the repair of DNA interstrand cross-links (ICLs) is thought to take place during S phase (3). The exact mechanism of repair is unknown, but it seems to involve the interplay of different pathways, with the homologous recombination machinery, translesion DNA polymerases, and the Fanconi anemia (FA) pathway all being required for ICL tolerance (4).FA is a genetically heterogeneous inherited disorder, which combines congenital abnormalities, bone marrow failure, and a marked cancer predisposition (5-8). FA cells are prone to spontaneous and damage-induced chromosomal aberrations and are notoriously hypersensitive to DNA interstrand cross-linking agents. FA proteins can be classified into three groups (8). Group I includes FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM. These eight FA proteins form a nuclear core complex (9-11) whose integrity is required for the conjugation of a ubiquitin moiety to the group II proteins, FANCI and FANCD2 (12,13). Group III consists of FANCD1 (BRCA2), FANCN (PALB2), and FANCJ (BRIP1), which do not play a role in FANCD2 monoubiquitination. BRCA2 regulates formation of RAD51 nucleoprotein filaments during homologous recombination (14, 15), PALB2 is necessary for the correct association of BRCA2 with chromatin (16), and BRIP1 is a BRCA1-associated DNA helicase that contributes to homologous recombination and cross-link repair (17, 18).The FA core complex protein FANCM can specifically bind to model replication forks and Holliday junctions and move the...

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“…The DA process tends to ensure replication of a damaged template while avoiding the polymerase to replicate through the lesion. This can be achieved by post replication recombinational repair or by a polymerase strand switch and is intrinsically error free [3]. TLS requires that a polymerase reads through the damaged base at the expense of replicational accuracy and is thus error prone in essence.…”

Section: Structural Insights Of Mmr Proteins Origin and Fate Of Mutatmentioning

confidence: 99%

Molecular Mechanisms of Mismatch Repair Genes in Cancer A Brief Review

Shilpa¹,

Lakshmi²

2016

Journal of Proteomics & Genomics

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Cancer, characterized by uncontrolled growth and cell division, has commanded tremendous efforts from the research fraternity in elucidating all plausible pathways that drive a normal cell into the oncogenic pathway. Designing new strategies and protocols for treatment of the disease have been extensively studied yet unsuccessful due to the fact that the diagnosis happens at a very late stage of malignancy that leaves less scope for complete revival and high risk of relapse. Amongst the varied reasons of cancer development, mutations; either inherited in the germ line or arising from changes in DNA sequence of somatic tissues during the life, are the major instigators. These mutations may abnormally enhance the function of protooncogenes, or erase effects of the tumor suppressor gene (TSG) products. Over expressed protooncogenes over-ride cell senescence and silenced TSGs derail the control over cell division and genetic stability. TSGs controlling cell growth are critical; however, genes involving DNA repair systems hold an equally important value in maintaining the cellular integrity and growth. The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The MMR system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops (IDLs) and heterologies generated during DNA replication and recombination. Failure to accomplish these functions may lead to cancer and are associated with tumor prone phenotypes. MMR proteins coordinate a complex network of physical and functional interactions and are also involved in activation of cell-cycle check point and induction of apoptosis during DNA damage. They also play a role in cell death by alkylating agents and other chemotherapeutic drugs. Inactivation of MMR genes by mutations or epigenetic silencing in hereditary and sporadic cancers is associated with mutator phenotype and inhibition of apoptosis. A deeper understanding of the molecular mechanism and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies. Introduction Molecular Mechanisms of Mismatch Repair Genes in Abstract

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A model for replication repair in mammalian cells

Cited by 422 publications

References 20 publications

The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination

The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination

Remodeling of DNA replication structures by the branch point translocase FANCM

Molecular Mechanisms of Mismatch Repair Genes in Cancer A Brief Review

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