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      Rad51 protects nascent DNA from Mre11 dependent degradation and promotes continuous DNA synthesis

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          Abstract

          The role of Rad51 in an unperturbed cell cycle has been difficult to dissect from its DNA repair function. Here, using electron microscopy (EM) to visualize replication intermediates (RIs) assembled in Xenopus laevis egg extract we show that Rad51 is required to prevent the accumulation of ssDNA gaps at replication forks and behind them. ssDNA gaps at forks arise from extended uncoupling of leading and lagging strand DNA synthesis. Instead, ssDNA gaps behind forks, which are exacerbated on damaged templates, result from Mre11 dependent degradation of newly synthesized DNA strands as they can be suppressed by inhibition of Mre11 nuclease activity. These findings reveal direct and unanticipated roles for Rad51 at replication forks demonstrating that Rad51 protects newly synthesised DNA from Mre11 dependent degradation and promotes continuous DNA synthesis.

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          Most cited references41

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          PCNA, the maestro of the replication fork.

          Inheritance requires genome duplication, reproduction of chromatin and its epigenetic information, mechanisms to ensure genome integrity, and faithful transmission of the information to progeny. Proliferating cell nuclear antigen (PCNA)-a cofactor of DNA polymerases that encircles DNA-orchestrates several of these functions by recruiting crucial players to the replication fork. Remarkably, many factors that are involved in replication-linked processes interact with a particular face of PCNA and through the same interaction domain, indicating that these interactions do not occur simultaneously during replication. Switching of PCNA partners may be triggered by affinity-driven competition, phosphorylation, proteolysis, and modification of PCNA by ubiquitin and SUMO.
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            Maintaining genome stability at the replication fork.

            Aberrant DNA replication is a major source of the mutations and chromosome rearrangements that are associated with pathological disorders. When replication is compromised, DNA becomes more prone to breakage. Secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymatic activities for their stabilization and subsequent advance. These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions. The mechanisms that operate in eukaryotic cells to promote replication fork integrity and coordinate replication with other aspects of chromosome maintenance are becoming clear.
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              Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.

              This review focuses on eukaryotic translesion synthesis (TLS) DNA polymerases, and the emphasis is on Saccharomyces cerevisiae and human Y-family polymerases (Pols) eta, iota, kappa, and Rev1, as well as on Polzeta, which is a member of the B-family polymerases. The fidelity, mismatch extension ability, and lesion bypass efficiencies of these different polymerases are examined and evaluated in the context of their structures. One major conclusion is that, despite the overall similarity of basic structural features among the Y-family polymerases, there is a high degree of specificity in their lesion bypass properties. Some are able to bypass a particular DNA lesion, whereas others are efficient at only the insertion step or the extension step of lesion bypass. This functional divergence is related to the differences in their structures. Polzeta is a highly specialized polymerase specifically adapted for extending primer termini opposite from a diverse array of DNA lesions, and depending upon the DNA lesion, it contributes to lesion bypass in a mutagenic or in an error-free manner. Proliferating cell nuclear antigen (PCNA) provides the central scaffold to which TLS polymerases bind for access to the replication ensemble stalled at a lesion site, and Rad6-Rad18-dependent protein ubiquitination is important for polymerase exchange.
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                Author and article information

                Journal
                101186374
                31761
                Nat Struct Mol Biol
                Nat. Struct. Mol. Biol.
                Nature structural & molecular biology
                1545-9993
                1545-9985
                7 January 2015
                10 October 2010
                November 2010
                26 January 2015
                : 17
                : 11
                : 1305-1311
                Affiliations
                [1 ]London Research Institute, Clare Hall laboratories, South Mimms, Herts EN6 3LD, UK
                [2 ]Institute of Molecular Cancer Research, University of Zuerich, Y 17 K 48, Winterthurerstrasse 190, CH-8057 Zuerich, Switzerland
                Author notes
                [* ] Corresponding authors: Vincenzo Costanzo, Vincenzo.costanzo@ 123456cancer.org.uk Massimo Lopes, lopes@ 123456imcr.uzh.ch

                AUTHOR CONTRIBUTIONS:

                Y.H. and A.R.C performed experiments; M.L and V.C conceived experiments and wrote the manuscript.

                Article
                EMS31895
                10.1038/nsmb.1927
                4306207
                20935632
                2c9b0b66-c7f4-4278-8b24-abeab56b988d

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Molecular biology
                Molecular biology

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