Mechanisms in Eukaryotic Mismatch Repair

Department of Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2006; 281(41):30305-9. DOI: 10.1074/jbc.R600022200
Source: PubMed

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    • "Single base–base mismatches that can result in base substitutions are primarily repaired by Msh2–Msh6 (MutS␣), with Msh2–Msh3 (MutS␤) having but a much smaller role [14] [15]. However, MutS␣ and MutS␤ can both participate in repairing insertion-deletion (indel) mutations containing one or two unpaired bases, and MutS␤ has primary responsibility for repairing mismatches containing multiple unpaired bases [16]. "
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    ABSTRACT: Mismatches generated during eukaryotic nuclear DNA replication are removed by two evolutionarily conserved error correction mechanisms acting in series, proofreading and mismatch repair (MMR). Defects in both processes are associated with increased susceptibility to cancer. To better understand these processes, we have quantified base selectivity, proofreading and MMR during nuclear DNA replication in Saccharomyces cerevisiae. In the absence of proofreading and MMR, the primary leading and lagging strand replicases, polymerase ɛ and polymerase δ respectively, synthesize DNA in vivo with somewhat different error rates and specificity, and with apparent base selectivity that is more than 100 times higher than measured in vitro. Moreover, leading and lagging strand replication fidelity rely on a different balance between proofreading and MMR. On average, proofreading contributes more to replication fidelity than does MMR, but their relative contributions vary from nearly all proofreading of some mismatches to mostly MMR of other mismatches. Thus accurate replication of the two DNA strands results from a non-uniform and variable balance between error prevention, proofreading and MMR. Copyright © 2015. Published by Elsevier B.V.
    DNA Repair 04/2015; 31. DOI:10.1016/j.dnarep.2015.04.006 · 3.11 Impact Factor
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    • "The role of mismatch repair proteins in repeat instability Mismatch repair (MMR) is normally involved in the repair of base mismatches or insertions/deletions (IDLs) (see Modrich, 2006 for review). It is initiated by recognition of the mismatch by MSH2/MSH6 (MutSa), a heterodimer that binds to single base mismatches and small IDLs or MSH2/MSH3 (MutSb), a complex that is involved in the repair of longer IDLs. "
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    ABSTRACT: Abstract The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.
    Critical Reviews in Biochemistry and Molecular Biology 01/2015; 50(2):1-26. DOI:10.3109/10409238.2014.999192 · 7.71 Impact Factor
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    • "MMR achieves this feat by a sequential mechanism comprising mismatch recognition, excision, and resynthesis steps. This process has been described in detail in several reviews (Kunkel and Erie, 2005; Jiricny, 2006; Modrich, 2006; Hsieh and Yamane, 2008). Briefly, the reaction commences by the binding of the MutS heterodimer to a mismatch (Figure 1). "
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    ABSTRACT: DNA is constantly under attack by a number of both exogenous and endogenous agents that challenge its integrity. Among the mechanisms that have evolved to counteract this deleterious action, mismatch repair (MMR) has specialized in removing DNA biosynthetic errors that occur when replicating the genome. Malfunction or inactivation of this system results in an increase in spontaneous mutability and a strong predisposition to tumor development. Besides this key corrective role, MMR proteins are involved in other pathways of DNA metabolism such as mitotic and meiotic recombination and processing of oxidative damage. Surprisingly, MMR is also required for certain mutagenic processes. The mutagenic MMR has beneficial consequences contributing to the generation of a vast repertoire of antibodies through class switch recombination and somatic hypermutation processes. However, this non-canonical mutagenic MMR also has detrimental effects; it promotes repeat expansions associated with neuromuscular and neurodegenerative diseases and may contribute to cancer/disease-related aberrant mutations and translocations. The reaction responsible for replication error correction has been the most thoroughly studied and it is the subject to numerous reviews. This review describes briefly the biochemistry of MMR and focuses primarily on the non-canonical MMR activities described in mammals as well as emerging research implicating interplay of MMR and chromatin.
    Frontiers in Genetics 08/2014; 5:287. DOI:10.3389/fgene.2014.00287
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