title: Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: McNairn
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
authors.forename: Vera D
authors.initials: VD
authors.lastname: Rinaldi
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 jcs92@cornell.edu.
authors.forename: John C
authors.identifier: 0000-0002-7294-1876
authors.initials: JC
authors.lastname: Schimenti
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D023902:Chromosome Pairing; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D005718:Gametogenesis / Q000235:genetics; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D064110:Minichromosome Maintenance Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C513032:Dmc1 protein, mouse; C000618216:MCMDC2 protein, mouse; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D064110:Minichromosome Maintenance Proteins
keywords: double strand break repair; meiosis; mouse; recombination; synapsis