Making chromosomes hot for breakage

Meiosis is a special cell division program that reduces the diploid chromosome set to a haploid set for sexual reproduction. Reductional segregation of homologous chromosomes is helped by physical linkages (crossovers) provided by recombina-tion. A long-standing problem in biology has been to understand how meiotic recom-bination is controlled, since its initiation by DNA double-strand breaks (DSBs) is a programmed damage that could be lethal and is highly organized temporally and spatially throughout the genome. Much of our current knowledge comes from work in fungi, notably the budding yeast Saccharomyces cerevisiae and the distantly related fission yeast Schizosaccharomyces pombe. As anticipated from well-known recombination hotspots, in both yeasts there are DSB hotspots. A major effort has been to map these hotspots and, more recently, the genome binding positions of the dozen or more proteins involved, to determine what makes particular genome sites hot for DSBs. DSB hotspot location is clearly related to other aspects of genome architecture. Hotspots are preferentially located in large intergenic regions in S. pombe and in promoter regions in S. cerevisiae. However, until recently no single factor seemed responsible for determining most DSB hotspots, and little was known about how the conserved topoisomerase-like protein Spo11 (Rec12 in S. pombe), which possesses the active site for DSB formation, is recruited or activated. We recently reported 2 that in fission yeast three proteins—Rec25, Rec27 and Mug20—are DSB hotspot determinants, since they bind with high specificity to hotspots in proportion to the frequency of DNA breakage and are required for most DSBs at hotspots (Fig. 1). These proteins interdependently co-localize in the nucleus (by fluorescence microscopy) and bind the same sites along the genome (by chroma-tin immunoprecipitation and microarray hybridization; ChIP-chip), suggesting they act as a complex. By ChIP-chip they bind to 86% of all hotspots (97% of the hottest two-thirds) independently of, and presumably before, DSB formation. Furthermore, in the absence of Rec27, DSBs are eliminated or strongly reduced at > 80% of hotspots. It was already known that meiotic chromosome components control recombina-tion. During meiosis, the synaptonemal complex (SC) binds sites along the entire chromosome length, forming a ladder-like structure with emanating loops and holds homologs together. S. pombe lacks an SC but has related structures called linear elements (LinEs) thought to extend across large parts of the chromosomes. Mutants lacking SC or LinE components, or cohesins required for their formation, are impaired in meiotic recombination and DSB …