Xrs2 C-terminus mediates Tel1-dependent meiotic double-strand break interference

Abstract

AbstractDuring meiosis, the programmed formation of DNA double-strand breaks (DSBs) by Spo11, a conserved topoisomerase-like protein, initiates homologous recombination that leads to crossovers between homologous chromosomes, essential for accurate segregation and genome evolution. Because DSBs are a threat to genome integrity, their number, distribution and timing of formation are regulated during the meiotic program. InS. cerevisiae, DSB interference prevents the coincident formation of DNA double-strand breaks (DSBs) in neighboring hotspots through a Tel1/ATM dependent mechanism that remains unexplored. Here, we demonstrate that Tel1 is recruited to meiotic DSBs hotspots in response to Spo11-DSB formation. Tel1 also localizes to chromosomal axis sites in a DSB-dependent manner, thus supporting the TLAC model that postulates meiotic DSBs are being formed within the chromosome axis environment. Tel1 recruitment to meiotic DSBs, DSB interference and the meiotic DNA damage checkpoint are dependent on both the Tel1-FATC domain and the C-terminal moiety of Xrs2, known to mediate Tel1-Xrs2 interaction in somatic cells. However, in a Xrs2 (FxF/Y) mutant DSBs interference remains functional despite Tel1 binding to DSB sites being significantly reduced and the Tel1-dependent DNA damage checkpoint abolished. Altogether, this work highlights the complex regulation of Tel1 multiple functions in meiotic cells, and fine-tuning through interaction with Xrs2.