Spo11 generates gaps through concerted cuts at sites of topological stress

Silvia Prieler, Doris Chen, Lingzhi Huang, Elisa Mayrhofer, Soma Zsótér, Magdalena Vesely, Jean Mbogning and Franz Klein ()
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Silvia Prieler: University of Vienna, Department of Chromosome Biology
Doris Chen: University of Vienna, Department of Chromosome Biology
Lingzhi Huang: University of Vienna, Department of Chromosome Biology
Elisa Mayrhofer: University of Vienna, Department of Chromosome Biology
Soma Zsótér: University of Vienna, Department of Chromosome Biology
Magdalena Vesely: University of Vienna, Department of Chromosome Biology
Jean Mbogning: University of Vienna, Department of Chromosome Biology
Franz Klein: University of Vienna, Department of Chromosome Biology

Nature, 2021, vol. 594, issue 7864, 577-582

Abstract: Abstract Meiotic recombination is essential for chromosome segregation at meiosis and fertility. It is initiated by programmed DNA double-strand breaks (DSBs) introduced by Spo11, a eukaryotic homologue of an archaeal topoisomerase (Topo VIA)1. Here we describe previously uncharacterized Spo11-induced lesions, 34 to several hundred base pair-long gaps, which are generated by coordinated pairs of DSBs termed double DSBs. Isolation and genome-wide mapping of the resulting fragments with single base-pair precision revealed enrichment at DSB hotspots but also a widely dispersed distribution across the genome. Spo11 prefers to cut sequences with similarity to a DNA-bending motif2, which indicates that bendability contributes to the choice of cleavage site. Moreover, fragment lengths have a periodicity of approximately (10.4n + 3) base pairs, which indicates that Spo11 favours cleavage on the same face of underwound DNA. Consistently, double DSB signals overlap and correlate with topoisomerase II-binding sites, which points to a role for topological stress and DNA crossings in break formation, and suggests a model for the formation of DSBs and double DSBs in which Spo11 traps two DNA strands. Double DSB gaps, which make up an estimated 20% of all initiation events, can account for full gene conversion events that are independent of both Msh2-dependent heteroduplex repair3,4 and the MutLγ endonuclease4. Because non-homologous gap repair results in deletions, and ectopically re-integrated double DSB fragments result in insertions, the formation of double DSBs is a potential source of evolutionary diversity and pathogenic germline aberrations.

Date: 2021
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DOI: 10.1038/s41586-021-03632-x

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