Roles for mismatch repair family proteins in promoting meiotic crossing over

Manhart, Carol M.; Alani, Eric

doi:10.1016/j.dnarep.2015.11.024

Cited by 101 publications

(116 citation statements)

References 168 publications

(185 reference statements)

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“…It is possible that MCMDC2 participates in promoting MSH4/5 function or other members of the ZMM complex that stabilize D-loops formed by invasion of single-stranded ends into homologous sequences (Manhart and Alani 2016). Such a scenario would link to the hypothesis that the Mei-MCM complex in Drosophila adapted to serve the function(s) of MSH4/5 (Kohl et al 2012).…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms regulating CO vs. NCO recombination is an area of intense study. Most of the CO events in both yeast and mice require proteins of the ZMM complex, including MSH4 and MSH5, which stabilize recombination intermediates and facilitate double Holliday junction formation after initial D-loops are formed by invasion of a singlestranded end of a resected DSB (Manhart and Alani 2016). In part, this is done by inhibiting the anti-CO activity of BLM helicase, which otherwise promotes synthesis-dependent strand annealing and NCO repair (Jessop et al 2006;Oh et al 2007;Holloway et al 2010;De Muyt et al 2012).…”

mentioning

confidence: 99%

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Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

McNairn¹,

Rinaldi²,

Schimenti

2017

Genetics

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The mammalian Mcm-domain containing 2 (Mcmdc2) gene encodes a protein of unknown function that is homologous to the minichromosome maintenance family of DNA replication licensing and helicase factors. Drosophila melanogaster contains two separate genes, the Mei-MCMs, which appear to have arisen from a single ancestral Mcmdc2 gene. The Mei-MCMs are involved in promoting meiotic crossovers by blocking the anticrossover activity of BLM helicase, a function presumably performed by MSH4 and MSH5 in metazoans. Here, we report that MCMDC2-deficient mice of both sexes are viable but sterile. Males fail to produce spermatozoa, and formation of primordial follicles is disrupted in females. Histology and immunocytological analyses of mutant testes revealed that meiosis is arrested in prophase I, and is characterized by persistent meiotic double-stranded DNA breaks (DSBs), failure of homologous chromosome synapsis and XY body formation, and an absence of crossing over. These phenotypes resembled those of MSH4/5-deficient meiocytes. The data indicate that MCMDC2 is essential for invasion of homologous sequences by RAD51-and DMC1-coated single-stranded DNA filaments, or stabilization of recombination intermediates following strand invasion, both of which are needed to drive stable homolog pairing and DSB repair via recombination in mice.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

McNairn¹,

Rinaldi²,

Schimenti

2017

Genetics

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“…MutLα (Mlh1-Pms1) is the primary endonuclease complex functioning in the MMR pathway, and MutLγ (Mlh1-Mlh3) plays only a minor role (58,59). In contrast, MutLγ has a major role in meiotic recombination during Holiday junction (HJ) resolution (60). Indeed, in vitro studies showed that MutLγ can bind to HJs and other heteroduplex structures independently of Msh2, although loading of the Msh2/ Msh3 complex enhanced MutLγ nicking of supercoiled DNA (43,61).…”

Section: Discussionmentioning

confidence: 99%

Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae

Freudenreich

2017

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

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CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies. Deletion of yeast cytosine deaminase Fcy1 significantly decreased the rate of CAG repeat fragility and contractions in the rnh1Δrnh201Δ background, indicating that Fcy1-mediated deamination is one cause of breakage and contractions in the presence of R-loops. Furthermore, base excision repair (BER) is responsible for causing CAG repeat contractions downstream of Fcy1, but not fragility. The Rad1/XPF and Rad2/XPG nucleases were also important in protecting against contractions, but through BER rather than nucleotide excision repair. Surprisingly, the MutLγ (Mlh1/Mlh3) endonuclease caused R-loop-dependent CAG fragility, defining an alternative function for this complex. These findings provide evidence that breakage at expanded CAG repeats occurs due to R-loop formation and reveal two mechanisms for CAG repeat instability: one mediated by cytosine deamination of DNA engaged in R-loops and the other by MutLγ cleavage. Since disease-causing CAG repeats occur in transcribed regions, our results suggest that R-loop-mediated fragility is a mechanism that could cause DNA damage and repeatlength changes in human cells.R-loop | CAG repeat instability | chromosome fragility | Fcy1 cytosine deaminase | Mlh1/Mlh3

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“…Some of these promote genome stability, such as suppression of homeologous recombination (by disrupting exchange between heteroduplex DNA substrates) [12,92], while others promote genome instability, such as expansion of triplet nucleotide repeat (TNR) sequences [93], processing of DNA oxidative damage lesions [94], and somatic hypermutation for antibody diversity [95]. For example, Msh2-Msh3 (MutSβ), which binds and initiates repair of insertion/deletion loops (post-replication or during recombination), also binds double strand/single strand junctions (for removal of 3’non-homologous tails in double strand break repair) [96], as well as secondary structures formed by repeat sequences (leading to TNR expansion and related neurological disorders) [97].…”

Section: Ongoing Research On How Atpase-coupled Actions Of Muts Anmentioning

confidence: 99%

Mismatch binding, ADP–ATP exchange and intramolecular signaling during mismatch repair

Hingorani

2016

DNA Repair

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The focus of this article is on the DNA binding and ATPase activities of the mismatch repair (MMR) protein, MutS—our current understanding of how this protein uses ATP to fuel its actions on DNA and initiate repair via interactions with MutL, the next protein in the pathway. Structure-function and kinetic studies have yielded detailed views of the MutS mechanism of action in MMR. How MutS and MutL work together after mismatch recognition to enable strand-specific nicking, which leads to strand excision and synthesis, is less clear and remains an active area of investigation.

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Roles for mismatch repair family proteins in promoting meiotic crossing over

Cited by 101 publications

References 168 publications

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog

Cytosine deamination and base excision repair cause R-loop–induced CAG repeat fragility and instability in Saccharomyces cerevisiae

Mismatch binding, ADP–ATP exchange and intramolecular signaling during mismatch repair

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