Mechanism of MutS Searching for DNA Mismatches and Signaling Repair

Teßmer, Ingrid; Yang, Yong; Zhai, Jie; Chungwei, Du,; Hsieh, Peggy; Hingorani, Manju; Erie, Dorothy A.

doi:10.1074/jbc.m805712200

Cited by 67 publications

(129 citation statements)

References 49 publications

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“…The mechanism that is most consistent with the data and the Brownian nature of molecular biology appears to be the molecular switch model (Gradia et al 1997(Gradia et al , 1999Fishel 1998Acharya et al 2003;Jeong et al 2011;Cho et al 2012;Gorman et al 2012;Qiu et al 2012;Spies 2013). Most, if not all, biochemical discrepancy can be traced to differences in the experimental conditions, an issue that persists today (Hall et al 2001;Drotschmann et al 2002;Tessmer et al 2008;Sass et al 2010;Tham et al 2013).…”

Section: Biochemical Activities Of the Mmr Proteinssupporting

confidence: 66%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans.

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Section: Biochemical Activities Of the Mmr Proteinssupporting

confidence: 66%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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“…This results in a conformational change in the protein which renders it competent for MMR, possibly by inhibiting ATP hydrolysis. (7) It is the MutS-DNA-ATP complex that interacts with MutL. (8) binding and hydrolysis by MutL do not seem to play a role in its interactions with MutS, they do govern its interaction with many of the downstream proteins required for completion of MMR: MutH, UvrD, DNA polymerase III (Pol III), and the b-sliding clamp (Fig.…”

Section: Post-replication Mismatch Repair: the Standard Repertoirementioning

confidence: 98%

MutL: conducting the cell's response to mismatched and misaligned DNA

Polosina

Cupples

2009

BioEssays

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Base pair mismatches in DNA arise from errors in DNA replication, recombination, and biochemical modification of bases. Mismatches are inherently transient. They are resolved passively by DNA replication, or actively by enzymatic removal and resynthesis of one of the bases. The first step in removal is recognition of strand discontinuity by one of the MutS proteins. Mismatches arising from errors in DNA replication are repaired in favor of the base on the template strand, but other mismatches trigger base excision or nucleotide excision repair (NER), or non-repair pathways such as hypermutation, cell cycle arrest, or apoptosis. We argue that MutL homologues play a key role in determining biologic outcome by recruiting and/or activating effector proteins in response to lesion recognition by MutS. We suggest that the process is regulated by conformational changes in MutL caused by cycles of ATP binding and hydrolysis, and by physiologic changes which influence effector availability.

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“…Two heterodimeric mismatch recognition complexes, MSH2/MSH6 and MSH2/MSH3, operate in mammals with distinct, but overlapping specificities (12)(13)(14). The crystal structure (15)(16)(17)(18), Atomic Force Microscopy (AFM) (19), and single molecule fluorescence resonant energy transfer (smFRET) (19,20) confirm that MSH2/ MSH6 and Escherichia coli (MutS) preferentially bind single base mismatches or two base pair bulges. MSH2/MSH3 can recognize some base-base mismatches (21), but has a higher apparent affinity and specificity for small DNA loops composed of 2-13 bases (12)(13)(14)(22)(23)(24).…”

mentioning

confidence: 89%

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Lang

Coats

Majka

et al. 2011

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

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Insertion and deletion of small heteroduplex loops are common mutations in DNA, but why some loops are prone to mutation and others are efficiently repaired is unknown. Here we report that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions. MSH2/MSH3 binds, bends, and dissociates from repair-competent loops to signal downstream repair. Repair-resistant Cytosine-Adenine-Guanine (CAG) loops adopt a unique DNA junction that traps nucleotide-bound MSH2/MSH3, and inhibits its dissociation from the DNA. We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.

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Mechanism of MutS Searching for DNA Mismatches and Signaling Repair

Cited by 67 publications

References 49 publications

Mismatch Repair during Homologous and Homeologous Recombination

Mismatch Repair during Homologous and Homeologous Recombination

MutL: conducting the cell's response to mismatched and misaligned DNA

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

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