Differential Association of the Conserved SUMO Ligase Zip3 with Meiotic Double-Strand Break Sites Reveals Regional Variations in the Outcome of Meiotic Recombination

Abstract

During the first meiotic prophase, programmed DNA double-strand breaks (DSBs) are distributed non randomly at hotspots along chromosomes, to initiate recombination. In all organisms, more DSBs are formed than crossovers (CO), the repair product that creates a physical link between homologs and allows their correct segregation. It is not known whether all DSB hotspots are also CO hotspots or if the CO/DSB ratio varies with the chromosomal location. Here, we investigated the variations in the CO/DSB ratio by mapping genome-wide the binding sites of the Zip3 protein during budding yeast meiosis. We show that Zip3 associates with DSB sites that are engaged in repair by CO, and Zip3 enrichment at DSBs reflects the DSB tendency to be repaired by CO. Moreover, the relative amount of Zip3 per DSB varies with the chromosomal location, and specific chromosomal features are associated with high or low Zip3 per DSB. This work shows that DSB hotspots are not necessarily CO hotspots and suggests that different categories of DSB sites may fulfill different functions.

Author Summary

For sexual reproduction, meiosis is an essential step ensuring the formation of haploid gametes from diploid precursors of the germline. This reduction in the genome's content is achieved through a specialized type of division, where a single round of DNA replication is followed by two successive rounds of chromosome segregation. The first round separates the homologs. For this to faithfully occur, homologous chromosomes pair with each other and experience recombination, catalyzed by the formation of programmed double-strand breaks (DSBs). Upon their repair, a subset of DSBs will generate crossovers, which result from an intermediate that creates a physical link between homologs and allows their correct segregation by the meiotic spindle. DSBs, as well as crossovers, do not occur randomly along chromosomes but at preferential places called hotspots. To ask if all DSB hotspots also give rise to high crossover frequency, we have systematically compared the map of DSBs with that of a protein, Zip3, which we show preferentially binds to DSB sites that are being repaired with a crossover. We discovered that several DSB hotspots rarely produce crossovers, meaning that the decision to repair a DSB with a crossover can be influenced by specific chromosomal features.