Article

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 · 3.36 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 · 5.81 Impact Factor
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    • "Mismatches can also adopt different structures under different neighboring sequence contexts [40]. Since DNA mismatch repair is a highly conserved process from prokaryotes to eukaryotes [41] [42] [43] [44] [45], structural studies of DNA mismatches will improve our understandings of the mismatch repair system and thereby the development of chemical shift prediction methods for mismatches will facilitate these studies. Among the different types of mismatches, AÁA and TÁT have been found to occur upon slippage in single strands of CAG and CTG repeats, respectively, during DNA replication, repair, and "
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    ABSTRACT: A proton chemical shift prediction scheme for B-DNA duplexes containing a T·T mismatch has been established. The scheme employs a set of T·T mismatch triplet chemical shift values, 5'- and 3'-correction factors extracted from reference sequences, and also the B-DNA chemical shift values predicted by Altona et al. The prediction scheme was tested by eight B-DNA duplexes containing T·T mismatches. Based on 560 sets of predicted and experimental proton chemical shift values, the overall prediction accuracy for non-labile protons was determined to be 0.07 ppm with an excellent correlation coefficient of 0.9996. In addition, the prediction accuracy for 96 sets of labile protons was found to be 0.22 ppm with a correlation coefficient of 0.9961. The prediction scheme developed herein can facilitate resonance assignments of B-DNA duplexes containing T·T mismatches and be generalized for the chemical shift prediction of other DNA mismatches. Our chemical shift data will also be useful for establishing structure-chemical shift information in B-DNA containing mismatches.
    Journal of Magnetic Resonance 09/2013; 252C:184-189. DOI:10.1016/j.jmr.2013.06.022 · 2.32 Impact Factor
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