Zip it up to shut it down

DNA double-strand breaks (DSBs) can be lethal to a cell. However, most sexually reproducing organisms deliberately induce a substantial amount of developmentally programmed DSBs that are subsequently repaired via homologous recombination in meiosis. The goal of this self-damage and self-repair process is to establish physical connections between homologous chromosomes, thereby ensuring accurate chromosome segregation and producing haploid germ cells (sperm and eggs) (Fig. 1). Recombination also disrupts the linkage of polymorphisms on the same chromosome and thus promotes genome diversity and evolution. Alterations in normal recombination patterns cause human aneuploidy, and these errors are a major cause of spontaneous abortion and congenital birth defects. Meiotic recombination does not occur randomly. It is more likely to happen in some genomic regions than others, largely due to nonrandom DSB distribution. There are large DSB-hot and -cold domains (tens of kilobases [kb]), within which are short regions called hotspots (typically several hundred base pairs wide), where DSBs preferentially form. This DSB landscape is shaped by a hierarchical combination of many factors including whole chromosome variation, large subchromosomal domains, cohesins and other chromosome structure proteins, chromatin structure, and local nucleotide composition. Notably, these factors act at different size scales and many of the molecular mechanisms connecting them to DSB formation are still not well understood. As potentially hazardous events, meiotic DSBs are tightly controlled in their timing, amount, and location. Emerging evidence in several organisms implies that the first step in recombination (DSB formation) is regulated by subsequent steps such as DSB repair. Recently, we explored such a feedback circuit in which homolog engagement shapes meiotic DSB number and spatial patterning in Saccharomyces cerevisiae (Fig. 1). For this purpose, we loosely define homolog engagement such that it could include the progression of recombination intermediates and/or the formation of synaptonemal complex (SC). (The SC is a meiosis-specific structure comprising the proteinaceous axes of a pair of homologous chromosomes held together by transverse filaments; it serves as a scaffold stabilizing the juxtaposition of homologous chromosomes and promotes the completion of recombination). Evidence in mice, flies and worms has suggested that negative feedback induced by engaging homologous chromosomes controls DSB formation. A test of this hypothesis arose from studies of the ZMM group of proteins (Zip1–4, Msh4–5, Mer3, Spo16, and Pph3). Mutants lacking ZMM proteins display defects in SC and recombination. We found that ZMM mutants formed a substantially greater number of DSBs, as judged by a variety of molecular and