Multiple Factors Insulate Msh2–Msh6 Mismatch Repair Activity from Defects in Msh2 Domain I

Kumar, Charanya; Piacente, Sarah C.; Sibert, Justin; Bukata, Andrew R.; O'Connor, Jaime; Alani, Eric; Surtees, Jennifer A.

doi:10.1016/j.jmb.2011.06.030

Cited by 18 publications

(23 citation statements)

References 71 publications

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“…Our recent observation that the human mismatch repair protein MLH1 is required to repair short CTG slip-outs and arrested on clustered slip-outs, might suggest that MLH1 is involved in CAG/CTG expansions, and MLH1 variants may have differential effects [94]. Polymorphisms in human MSH2 have been identified in patients with hereditary non-polyposis colorectal cancer that are thought to inactivate the function of the MSH2–MSH3 complex but not the MSH2–MSH6 complex; leading to altered frameshift mutations in yeast [95], [96]. Polymorphic variants of hMSH3 have been significantly linked to cancer and radiation sensitivity [97]–[100].…”

Section: Discussionmentioning

confidence: 99%

MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

et al. 2013

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Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)∼100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases.

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Section: Discussionmentioning

confidence: 99%

MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

et al. 2013

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“…An early study reported that the expression of Msh6 is approximately tenfold higher than Msh2, whereas a recent study of mice found that the expression of Msh3 is higher than expression of Msh6 in most tissues, with similar levels of Msh2 and Msh6 in testis (137). The number of MMR proteins has been measured in yeast using quantitative western blots of TAP (tandem affinity purification) tagged and untagged MMR proteins (28, 63). The number of proteins found in Saccharomyces cerevisiae is ~1,300 for Msh2, 1,600–5,000 for Msh6, ~740 for Msh3, ~320 for Mlh1, and ~520 for Pms1.…”

Section: Mechanisms Of Mismatch Repair In Relation To Replicationmentioning

confidence: 99%

Eukaryotic Mismatch Repair in Relation to DNA Replication

2015

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Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome.

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“…Msh3 mismatch specificity can be imparted to yeast MutSa by replacing the Msh6 mismatch-binding domain (MBD) with the presumptive Msh3 MBD; the reverse domain swap, however, does not yield a functional complex (Shell et al 2007b). A separation-of-function msh2 allele that differentially affects MutSa and MutSb provides additional evidence that these complexes sense and/or respond to mismatches differently (Lee et al 2007;Kumar et al 2011).…”

Section: Muts Homologsmentioning

confidence: 99%

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

2013

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DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage.

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Multiple Factors Insulate Msh2–Msh6 Mismatch Repair Activity from Defects in Msh2 Domain I

Cited by 18 publications

References 71 publications

MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

Eukaryotic Mismatch Repair in Relation to DNA Replication

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

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