Meiotic DSB patterning: A multifaceted process

Abstract

Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that collectively ensure fruitful and appropriate levels of genetic exchange without risk to cellular survival. Within this article we focus upon an emerging element of this control—spatial regulation—detailing recent advances made in understanding how DSBs are evenly distributed across the genome, and present a unified view of the underlying patterning mechanisms employed.

Numerical and Spatial Patterning of Yeast Meiotic DNA Breaks by Tel1

“…Nonetheless, the negative feedback regulation of DSB numbers via ATM/Tel1 and the fact that this regulation contributes to shaping the DSB landscape are common threads linking these evolutionarily distant species. It has been argued that the elements that shape DSB distributions can be divided into "intrinsic" factors (the DSB machinery and its chromatin substrate) and more "extrinsic" (or "reactive") factors that provide homeostatic feedback regulation Cooper et al 2016). Our results place Tel1 firmly on the list of such extrinsic factors and illustrate the complex interplay between Tel1-dependent and ZMM-dependent pathways for controlling both the number and distribution of DSBs.…”

“…Also consistent with this view, the 6-h tel1Δ Spo11-oligo map displayed only relatively modest changes relative to wild type, indicating that the net effect of Tel1 absence is that the extra DSBs end up accumulating largely in the same places as they do in wild type. It is possible that Tel1 dependence varies between genomic locations, but we also consider it likely that a hotspot with relatively high DSB frequency is necessary to detect this behavior (Zhang et al 2011;Zhu and Keeney 2015;Cooper et al 2016). This, in turn, may explain why studies of medium-strength natural hotspots failed to display similar interactions between neighbors (Bullard et al 1996;Zhu and Keeney 2015).…”

“…To balance the positive (chromosome segregation promoting) and negative (mutagenic) roles of meiotic DSBs, cells possess overlapping, homeostatic pathways that control the number and repair of DSBs and, in doing so, shape the recombination distribution Cooper et al 2016). The DSB "landscape," i.e., the distribution of DSBs across the genome, is defined by complex hierarchical influences operating over different size scales Lam and Keeney 2015a;Cooper et al 2016).…”

“…In Saccharomyces cerevisiae, most hotspots correspond to evolutionarily conserved nucleosome-depleted promoters (Lam and Keeney 2015b). However, the factors shaping the DSB landscape at larger size scales remain poorly understood, particularly those factors related to the intersecting feedback mechanisms that regulate Spo11 activity Cooper et al 2016).…”

Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1

“…The DSB "landscape," i.e., the distribution of DSBs across the genome, is defined by complex hierarchical influences operating over different size scales Lam and Keeney 2015a;Cooper et al 2016). Some genomic regions, encompassing tens to hundreds of kb, experience more or less DSB formation than others, and within such DSB-"hot" and DSB-"cold" domains, DSBs are particularly enriched in small (typically <250 bp) regions known as "hotspots."…”