Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice Journal Article


Authors: Dereli, I.; Stanzione, M.; Olmeda, F.; Papanikos, F.; Baumann, M.; Demir, S.; Carofiglio, F.; Lange, J.; de Massy, B.; Baarends, W. M.; Turner, J.; Rulands, S.; Tóth, A.
Article Title: Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice
Abstract: In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation. © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Keywords: signal transduction; genetics; cell cycle protein; mouse; pachytene; animal; meiosis; metabolism; animals; cell cycle proteins; mice; physiology; atm protein; dna breaks, double-stranded; double stranded dna break; feedback, physiological; chromosome pairing; pachytene stage; sex chromosome; gametogenesis; sex chromosomes; ataxia telangiectasia mutated proteins; aaa protein; atr protein, mouse; trip13 protein, mouse; physiological feedback; atpases associated with diverse cellular activities
Journal Title: Nucleic Acids Research
Volume: 49
Issue: 5
ISSN: 0305-1048
Publisher: Oxford University Press  
Date Published: 2021-03-18
Start Page: 2609
End Page: 2628
Language: English
DOI: 10.1093/nar/gkab082
PUBMED: 33619545
PROVIDER: scopus
PMCID: PMC7969012
DOI/URL:
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
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  1. Julian Lange
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