Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms
- Lukasz Wojtasz1,
- Jeffrey M. Cloutier2,
- Marek Baumann1,
- Katrin Daniel1,
- János Varga3,
- Jun Fu4,
- Konstantinos Anastassiadis5,
- A. Francis Stewart4,
- Attila Reményi3,
- James M.A. Turner2 and
- Attila Tóth1,6
- 1Institute of Physiological Chemistry, Technische Universität Dresden, Dresden 01307, Germany;
- 2Divisional of Developmental Genetics, MRC National Institute for Medical Research, London, NW7 1AA, United Kingdom;
- 3Department of Biochemistry, Institute of Biology, Eötvös Loránd University, 1117 Budapest, Hungary;
- 4Genomics,
- 5Center for Regenerative Therapies Dresden, BioInnovationsZentrum, Technische Universität Dresden, Dresden 01307, Germany
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.
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Footnotes
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↵6 Corresponding author.
E-mail attila.toth{at}mailbox.tu-dresden.de.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.187559.112.
- Received January 30, 2012.
- Accepted March 19, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press