title: Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms.
abstract: Meiotic crossover formation involves the repair of programmed DNA double-strand breaks (DSBs) and synaptonemal complex (SC) formation. Completion of these processes must precede the meiotic divisions in order to avoid chromosome abnormalities in gametes. Enduring key questions in meiosis have been how meiotic progression and crossover formation are coordinated, whether inappropriate asynapsis is monitored, and whether asynapsis elicits prophase arrest via mechanisms that are distinct from the surveillance of unrepaired DNA DSBs. We disrupted the meiosis-specific mouse HORMAD2 (Hop1, Rev7, and Mad2 domain 2) protein, which preferentially associates with unsynapsed chromosome axes. We show that HORMAD2 is required for the accumulation of the checkpoint kinase ATR along unsynapsed axes, but not at DNA DSBs or on DNA DSB-associated chromatin loops. Consistent with the hypothesis that ATR activity on chromatin plays important roles in the quality control of meiotic prophase, HORMAD2 is required for the elimination of the asynaptic Spo11(-/-), but not the asynaptic and DSB repair-defective Dmc1(-/-) oocytes. Our observations strongly suggest that HORMAD2-dependent recruitment of ATR to unsynapsed chromosome axes constitutes a mechanism for the surveillance of asynapsis. Thus, we provide convincing evidence for the existence of a distinct asynapsis surveillance mechanism that safeguards the ploidy of the mammalian germline.
authors.affiliation: Institute of Physiological Chemistry, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtasz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Cloutier
authors.forename: Marek
authors.initials: M
authors.lastname: Baumann
authors.forename: Katrin
authors.initials: K
authors.lastname: Daniel
authors.forename: János
authors.initials: J
authors.lastname: Varga
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.forename: Attila
authors.initials: A
authors.lastname: Reményi
authors.forename: James M A
authors.initials: JM
authors.lastname: Turner
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D023902:Chromosome Pairing / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D005260:Female; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D013573:Synaptonemal Complex / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C513032:Dmc1 protein, mouse; C546539:HORMAD2 protein, mouse; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins