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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.
Highlights
Chromosome numbers are halved in germ cells during meiosis as a single round of pre-meiotic DNA replication is followed by two rounds of chromosome segregations
To elucidate the spatiotemporal control of the double-strand breaks (DSBs) 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
DSBs and three DNA damage response (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
Summary
Chromosome numbers are halved in germ cells during meiosis as a single round of pre-meiotic DNA replication is followed by two rounds of chromosome segregations. Chromosome segregation in the first meiotic division mechanistically requires conjoining of homologous copies (homologues) of each chromosome by the formation of physical linkages in the first meiotic prophase (reviewed in [1]). Physical linkages between homologues rely on reciprocal inter-homologue DNA exchanges, called crossovers. Meiotic homologous recombination generates crossovers by the repair of programmed DNA double-stranded breaks (DSBs), whose induction at the start of meiosis depends on the topoisomerase-like enzyme, SPO11, and its co-factor TOPOVIBl [2,3,4,5,6,7]. DSBs both constitute a potentially toxic DNA damage and enable meiotic recombination, DSB formation is under tight spatiotemporal control in meiosis [8,9,10,11,12].
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