Mismatch Repair Inhibits Homeologous Recombination via Coordinated Directional Unwinding of Trapped DNA Structures

Tham, Khek-Chian; Hermans, Nicolaas; Winterwerp, H.H.K.; Cox, Michael M.; Wyman, Claire; Kanaar, Roland; Lebbink, Joyce H.G.

doi:10.1016/j.molcel.2013.07.008

Cited by 50 publications

(59 citation statements)

References 59 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 Proteinsmentioning

confidence: 59%

“…Both approaches reconstitute the initial steps and/or intermediates in homeologous recombination. One approach has been to determine any inhibitory role for the E. coli MMR machinery on DNA strand exchange and D-loop formation catalyzed by EcRecA (Worth et al 1994;Tham et al 2013). Two different recombinase assays have been used to observe homologous pairing and strand exchange in vitro: (1) a three-strand system in which RecA/ RAD51 catalyzes the exchange of homologous strands between a double-stranded linear DNA and a large circular ssDNA, and (2) RecA/ RAD51-catalyzed formation of a D-loop between a relatively short linear ssDNA and a supercoiled circular DNA .…”

Section: Mismatch Repairmentioning

confidence: 99%

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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 Proteinsmentioning

confidence: 59%

Section: Mismatch Repairmentioning

confidence: 99%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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“…Two distinct species of the jointmolecule intermediates are formed during the strand exchange reaction (34). The early joint-molecule intermediates are known to migrate faster in the agarose gel compared with those intermediates formed further along reaction progression toward the nicked circular product (34). The stimulation of strand exchange activity can be attributed to the efficient conversion of early joint-molecule intermediates, which were observed in much higher amounts for the wild-type protein and RAD51 Y54F compared with RAD51 Y54pCMF (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…S3B). Two distinct species of the jointmolecule intermediates are formed during the strand exchange reaction (34). The early joint-molecule intermediates are known to migrate faster in the agarose gel compared with those intermediates formed further along reaction progression toward the nicked circular product (34).…”

Section: Resultsmentioning

confidence: 99%

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Subramanyam

Ismail

Bhattacharya

et al. 2016

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

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The DNA strand exchange protein RAD51 facilitates the central step in homologous recombination, a process fundamentally important for accurate repair of damaged chromosomes, restart of collapsed replication forks, and telomere maintenance. The active form of RAD51 is a nucleoprotein filament that assembles on single-stranded DNA (ssDNA) at the sites of DNA damage. The c-Abl tyrosine kinase and its oncogenic counterpart BCR-ABL fusion kinase phosphorylate human RAD51 on tyrosine residues 54 and 315. We combined biochemical reconstitutions of the DNA strand exchange reactions with total internal reflection fluorescence microscopy to determine how the two phosphorylation events affect the biochemical activities of human RAD51 and properties of the RAD51 nucleoprotein filament. By mimicking RAD51 tyrosine phosphorylation with a nonnatural amino acid, p-carboxymethyl-L-phenylalanine (pCMF), we demonstrated that Y54 phosphorylation enhances the RAD51 recombinase activity by at least two different mechanisms, modifies the RAD51 nucleoprotein filament formation, and allows RAD51 to compete efficiently with ssDNA binding protein RPA. In contrast, Y315 phosphorylation has little effect on the RAD51 activities. Based on our work and previous cellular studies, we propose a mechanism underlying RAD51 activation by c-Abl/BCR-ABL kinases.RAD51 recombinase | c-Abl tyrosine kinase | homologous recombination | single-molecule total internal reflection fluorescence microscopy | phosphorylation T he DNA in the human genome is constantly subjected to damage. This damage is a byproduct of normal cellular metabolism, exposure to radiation, and environmental mutagens (1). Homologous recombination (HR) and the pathways that use the machinery of HR are responsible for the accurate repair of the most deleterious DNA lesions, including double-stranded DNA breaks (DSBs), interstrand DNA cross-links, and damaged replication forks, and thereby contribute to maintenance of the stable genome (2-5). HR also plays an important role in telomere maintenance (6). HR, a process highly conserved throughout evolution, is carried out through a precisely coordinated and tightly regulated series of events. The key step in HR is the assembly of a RecA-family recombinase (phage UvsX, bacterial RecA, archaeal RadA, or eukaryotic RAD51) onto resected single-stranded DNA (ssDNA). The recombinase forms a nucleoprotein filament that then invades homologous duplex DNA, resulting in a displacement loop structure that can be used as a primer for synthesis using the intact duplex as a template. Similar to its bacterial and yeast homologs, the human RAD51 binds ssDNA in an ATP-dependent manner (7). The nucleoprotein filament formed by the ATP-bound RAD51 is arranged such that each RAD51 monomer binds three nucleotides, forming the pairing unit in these reactions (8). Beyond these basic attributes, the characteristics of human RAD51 protein differ significantly from its archaeal, bacterial, and yeast homologs.The critical role of HR requires all steps of this process ...

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“…MutS and MutL inhibit RecA-catalyzed strand transfer between heterologous DNAs in vitro presumably by blocking the RecA-mediated branch migration (33) and act in concert with UvrD helicase to antagonize illegitimate recombination (34). These studies brought forward the idea that the MMR proteins may operate in the context of the recombination intermediate, where the structure of the D-loop and the presence of the postsynaptic filament may interfere with the formation or stability of the MutS-mismatch complex.…”

Section: Significancementioning

confidence: 99%

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Honda

Okuno

Hengel

et al. 2014

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

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High fidelity homologous DNA recombination depends on mismatch repair (MMR), which antagonizes recombination between divergent sequences by rejecting heteroduplex DNA containing excessive nucleotide mismatches. The hMSH2-hMSH6 heterodimer is the first responder in postreplicative MMR and also plays a prominent role in heteroduplex rejection. Whether a similar molecular mechanism underlies its function in these two processes remains enigmatic. We have determined that hMSH2-hMSH6 efficiently recognizes mismatches within a D-loop recombination initiation intermediate. Mismatch recognition by hMSH2-hMSH6 is not abrogated by human replication protein A (HsRPA) bound to the displaced single-stranded DNA (ssDNA) or by HsRAD51. In addition, ATP-bound hMSH2-hMSH6 sliding clamps that are essential for downstream MMR processes are formed and constrained within the heteroduplex region of the D-loop. Moreover, the hMSH2-hMSH6 sliding clamps are stabilized on the Dloop by HsRPA bound to the displaced ssDNA. Our findings reveal similarities and differences in hMSH2-hMSH6 mismatch recognition and sliding-clamp formation between a D-loop recombination intermediate and linear duplex DNA.

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Mismatch Repair Inhibits Homeologous Recombination via Coordinated Directional Unwinding of Trapped DNA Structures

Cited by 50 publications

References 59 publications

Mismatch Repair during Homologous and Homeologous Recombination

Mismatch Repair during Homologous and Homeologous Recombination

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

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