MCM9 Is Required for Mammalian DNA Mismatch Repair

Traver, Sabine; Coulombe, Philippe; Peiffer, Isabelle; Hutchins, James R. A.; Kitzmann, Magali; Latreille, Daniel; Méchali, Marcel

doi:10.1016/j.molcel.2015.07.010

Cited by 67 publications

(72 citation statements)

References 59 publications

(92 reference statements)

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“…However, there are additional MCM family members that function outside of the core MCM2-7 replicative helicase complex. MCM8 and MCM9 function in DNA repair and homologous recombination (Park et al 2013;Traver et al 2015). Both are dispensable for DNA replication in mice, but MCM8-and MCM9-deficient cells exhibit defects in homologous recombination repair in response to DNA damage (Hartford et al 2011;Lutzmann et al 2012;Nishimura et al 2012;Park et al 2013;Lee et al 2015;Luo and Schimenti 2015).…”

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confidence: 99%

“…Both are dispensable for DNA replication in mice, but MCM8-and MCM9-deficient cells exhibit defects in homologous recombination repair in response to DNA damage (Hartford et al 2011;Lutzmann et al 2012;Nishimura et al 2012;Park et al 2013;Lee et al 2015;Luo and Schimenti 2015). Surprisingly, Mcm9, which is absent from Drosophila, is also required for DNA mismatch repair and this may actually be its primary function (Traver et al 2015). Mcm8 null mice of both sexes are sterile due to defects in homologous recombination repair during meiotic prophase I (Lutzmann et al 2012), whereas Mcm9 mutant mice are defective in primordial germ cell proliferation that leads to reduced (males) or absent (females) germ cells (Hartford et al 2011;Lutzmann et al 2012).…”

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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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confidence: 99%

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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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“…No variants were located in the Walker A or R-finger motifs (Figure 1) that are critical for helicase activity [12,22].…”

Section: Patients (4/109) This Variant Was Still Classified As a Varmentioning

confidence: 99%

“…MCM9 recruitment to chromatin is MSH2-dependent and stimulates MLH1 chromatin binding, and cells lacking the protein develop MMR deficiency and MSI [12]. [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic germline MCM9 variants are rare in Australian Lynch-like syndrome patients

et al. 2016

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Highlights First screen of MCM9 for germline variants in Lynch-like syndrome patients. Fifteen variants identified in a cohort of 109 Lynch-like syndrome patients. Variants included 6 common SNPs and 9 variants of unknown significance. with LLS and variants were cross-referenced with three population-based databases (dbSNP144, 1000 Genomes, ExAC). The functional effect of variants was assessed in silico with PolyPhen-2, SIFT and CONDEL. Fifteen variants that included six common SNPs and nine variants of unknown significance (VUS) were identified.. We conclude that VUS occur in MCM9 in a small proportion of LLS patients and MCM9 mutations are unlikely to explain most LLS cases.

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“…Additional evidence suggests that the MCMs, in particular MCM3 [14], may directly influence DNA replication checkpoints to ensure replicative integrity [15][16][17][18][19], although the precise role MCMs play in the modulation of DNA repair pathways is still unclear. Other eukaryotic MCM paralogues have been shown to have a role in the repair of meiotic DNA breaks in mice [20], mammalian DNA mismatch repair [21] and the facilitation of DNA repair at homologous recombination sites [22].…”

Section: Introductionmentioning

confidence: 99%

Non-essential MCM-related proteins mediate a response to DNA damage in the archaeon Methanococcus maripaludis

Walters

Chong

2017

Microbiology

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The single minichromosome maintenance (MCM) protein found in most archaea has been widely studied as a simplified model for the MCM complex that forms the catalytic core of the eukaryotic replicative helicase. Organisms of the order Methanococcales are unusual in possessing multiple MCM homologues. The Methanococcus maripaludis S2 genome encodes four MCM homologues, McmA-McmD. DNA helicase assays reveal that the unwinding activity of the three MCM-like proteins is highly variable despite sequence similarities and suggests additional motifs that influence MCM function are yet to be identified. While the gene encoding McmA could not be deleted, strains harbouring individual deletions of genes encoding each of the other MCMs display phenotypes consistent with these proteins modulating DNA damage responses. M. maripaludis S2 is the first archaeon in which MCM proteins have been shown to influence the DNA damage response.

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MCM9 Is Required for Mammalian DNA Mismatch Repair

Cited by 67 publications

References 59 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

Pathogenic germline MCM9 variants are rare in Australian Lynch-like syndrome patients

Non-essential MCM-related proteins mediate a response to DNA damage in the archaeon Methanococcus maripaludis

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