Progress has been made in the following areas: Initiation of meiotic recombination: Meiotic recombination is initiated by DNA double-strand breaks (DSBs); both the location and timing of break formation is tightly controlled.
Our aim i s to determine the substrate requirements of proteins that form DSBs, and the factors that control their location, frequency and timing. Current research is directed at determining the chromosome structural elements that determine where DSBs do and do not form. We developed a novel technique to isolate intermediates in double-strand break-repair, based on their partially single-stranded DNA content. We applied this method to a microarray-based whole genome analysis to recombination intermediate distributions, and have determined the true distribution of meiotic recombination initiation events across the genome. Our data show that meiotic DSBs are much more evenly distributed than had been previously believed, and also illuminate the mechanism of DSB formation and repair during meiosis. Mechanism of meiotic recombination: We have developed techniques to isolate and characterize unstable intermediates in meiotic recombination, and have used these techniques to demonstrate that the two classes of meiotic recombination (events associated with crossing-over versus events not accompanied by crossing-over) proceed by distinct molecular mechanisms. Our current aim is to determine the repair proteins that participate in both pathways, that are unique to one or the other pathway, and that determine the choice between crossover and noncrossover recombination. Recent experiments identify the Sgs1 helicase (the budding yeast homolog of the helicase mutated in Bloom's syndrome) and the Mus81/Mms4 structure-specific endonuclease as playing a critical role in controlling meiotic recombination. In the absence of these two proteins, abnormal recombination intermediates accumulate and block chromosome segregation. Using a system that allows induced expression of target proteins late in meiosis, we showed that Mus81/Mms4 is resolves these abnormal intermediates after they are formed, while Sgs1 prevents their formation. Because mutants lacking both Sgs1 and Mus81/Mms4 are inviable, it is likely that these two proteins play similar roles in chromosome metabolism during the mitotic cell cycle. This subject is a subject of current investigation. We previously had shown that upregulation of a class of meiotically-expressed genes (middle-meiosis genes) was a critical step in the resolution of recombination intermediates as crossovers. We have now identified Cdc5, the budding yeast polo-like kinase, as the sole member of the >200 middle-meiosis genes that is required for both crossover formation and for the disassembly of meiosis-specific chromosome structures in advance of the meiotic divisions. Identification of the functional Cdc5 target is underway.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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National Cancer Institute Division of Basic Sciences
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Nakamura, Asako; Sedelnikova, Olga A; Redon, Christophe et al. (2006) Techniques for gamma-H2AX detection. Methods Enzymol 409:236-50
Jessop, Lea; Allers, Thorsten; Lichten, Michael (2005) Infrequent co-conversion of markers flanking a meiotic recombination initiation site in Saccharomyces cerevisiae. Genetics 169:1353-67
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