Persistent DNA-break potential near telomeres increases initiation of meiotic recombination on short chromosomes

Abstract

Faithful meiotic chromosome inheritance and fertility rely on the stimulation of meiotic crossover recombination by potentially genotoxic DNA double-strand breaks (DSBs). To avoid excessive damage, feedback mechanisms down-regulate DSBs, likely in response to initiation of crossover repair. In Saccharomyces cerevisiae , this regulation requires the removal of the conserved DSB-promoting protein Hop1/HORMAD during chromosome synapsis. Here, we identify privileged end-adjacent regions (EARs) spanning roughly 100 kb near all telomeres that escape DSB down-regulation. These regions retain Hop1 and continue to break in pachynema despite normal synaptonemal complex deposition. Differential retention of Hop1 requires the disassemblase Pch2/TRIP13, which preferentially removes Hop1 from telomere-distant sequences, and is modulated by the histone deacetylase Sir2 and the nucleoporin Nup2. Importantly, the uniform size of EARs among chromosomes contributes to disproportionately high DSB and repair signals on short chromosomes in pachynema, suggesting that EARs partially underlie the curiously high recombination rate of short chromosomes.

Separable roles of the DNA damage response kinase Mec1(ATR) and its activator Rad24(RAD17) within the regulation of meiotic recombination

“…No further increase in recombination was observed in the ndt80AR msh2 Δ double strain (Fig 2A), suggesting that there may be an upper limit to recombination frequency in these backgrounds. Interestingly, extending prophase length, but not MSH2 deletion, skews recombination towards subtelomeres (Fig S3A-B)—regions that are both less compacted as measured by Hi-C [43], and retain disproportionately high levels of DSB formation at pachytene [44].…”

Topoisomerases modulate the timing of meiotic DNA breakage and chromosome morphogenesis inSaccharomyces cerevisiae

“…Overlapping Hop1 and Zip1 signals and DAPI train tracks are indicative of a defect in proper Hop1 removal and a hallmark of mutants that fail to recruit the AAA+ ATPase Pch2 (Borner et al, 2008;San-Segundo & Roeder, 1999;Subramanian et al, 2016;Subramanian et al, 2019). The persistence of Hop1 on fully synapsed chromosomes, in turn, impairs timely DSB repair (Subramanian et al, 2016).…”

Crossing and zipping: molecular duties of the ZMM proteins in meiosis

“…Accordingly, COs are more reduced on small chromosomes (such as chromosome III) than on large chromosomes (such as chromosome VIII), where CO frequencies in certain zmm mutants may exceed those observed in the wild type (Chen et al 2015;Serrentino et al 2013). One hypothesis is that failure to synapse results in continued Spo11 activity disproportionately increasing DSBs along larger chromosomes Subramanian et al 2019;Thacker et al 2014). Approximately half of these breaks can be repaired as COs via the SSNs and they differ from ZMM COs in that they do not interfere.…”