Mechanism and regulation of meiotic recombination

Homologous recombination in meiosis is essential for genome integrity during sexual reproduction, but is also a powerful determinant of genome evolution and puts cells at risk for mutation and chromosome rearrangements. Meiotic recombination initiates with DNA double-strand breaks (DSBs) made by Spo11. Cells ensure that DSBs are made at the right times, places, and numbers to maximize repair efficiency and minimize risks of deleterious outcomes. This research program aims to understand the molecular mechanisms of meiotic DSB formation and of the processes that regulate DSBs and recombination. Mouse and the yeast S. cerevisiae will be used to explore these critical aspects of chromosome biology. Specific areas of inquiry include the following: · A complex network of pathways controls the number, timing, and distribution of DSBs. In one pathway, the DNA damage-response kinase ATM inhibits formation of additional breaks. A second pathway suppresses DSB formation in places where homologous chromosomes have successfully engaged one another. An important challenge is to understand the mechanisms underlying these pathways. · DSB locations are nonrandom, and this DSB “landscape” has important consequences for heritability and genome stability. The factors shaping the DSB landscape remain poorly understood, but recent advances inform mechanistic hypotheses about the roles of both chromosome-intrinsic and trans-acting factors. These hypothe- ses will be tested using powerful methods for mapping DSB distributions genome-wide at nucleotide resolution. · An essential step in the repair of DSBs by recombination is the exonucleolytic processing of DNA ends, but little is known about the mechanism. An innovative new whole-genome assay for DSB resection will be exploited to define how resection is carried out, how it is regulated, and how it overcomes the barrier to nucleases posed by chromatin. · Erroneous, non-allelic recombination between repetitive DNA sequences yields chromosome rearrange- ments that can be passed on to offspring. Recent work identified genomic locations in mice that are prone to such errors and developed tools to characterize and quantify rearrangements. Important challenges now are to understand the mechanisms of this mutagenic recombination and to understand how cells avoid these errors. · In male mammals, segregation of the sex chromosomes is especially challenging because the X and Y chro- mosomes share only a small region of homology (the pseudoautosomal region, or PAR) within which recombi- nation must occur. Defects in PAR recombination cause sterility or sex chromosome missegregation. Recent work has revealed that the PAR develops complex, dynamic structures during meiosis. Cis- and trans-acting factors critical for this behavior have also been uncovered. Key questions will be addressed concerning the mechanisms that ensure sex chromosome recombination and segregation.