Our long term goal is to understand how genetic recombination contributes to the faithful inheritance of chromosomes. Genetic recombination is of central importance to sexually reproducing organisms, since crossover recombination events between the DNA molecules of homologous chromosomes, and the resulting chiasmata, are necessary for proper chromosome segregation at the meiosis I division. Failure to form crossovers leads to chromosome missegregation and consequent aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Meiotic crossing over is accomplished by deliberate induction of double-strand DNA breaks (DSBs), followed by repair of these breaks using meiosis-specific modifications of DSBR pathways in the context of meiosis-specific chromosome architecture. This process is subject to multiple levels of regulation to ensure that DSBs are formed and repaired in an appropriate temporal context, both to avoid posing a threat to genome integrity and to guarantee that each chromosome pair will undergo the obligate crossover required to promote homolog segregation. We are investigating the mechanisms that promote and limit the formation of interhomolog crossovers (COs) and that regulate DSB formation in the nematode C. elegans, a simple metazoan organism that is especially amenable to combining sophisticated cytological and genetic approaches in a single experimental system, and in which robust crossover control mechanisms are known to operate. The proposed work will exploit recent advances that provide the means to visualize the sites of nascent meiotic CO events in both live and fixed germ cells using GFP:COSA-1, to screen directly for mutants with impaired CO interference, to experimentally induce recombination events at defined sites and/or defined time frames, to target recombination proteins to defined sites, and to capture DNA associated with CO sites. One major goal is to identify factors and mechanisms that contribute to CO interference, and to understand the interplay between mechanisms that antagonize CO formation and mechanisms that promote CO designation and progressive differentiation of CO sites. A related goal is to uncover features that may bias the outcome of CO/NCO designation. Another goal is to understand the basis of dynamic regulation of repair partner utilization during meiotic progression. Finally, we will analyze the architecture of the meiotic DSB regulation network to understand how DSB formation is modulated to maintain a balance between the beneficial effects of COs and the potential harmful consequences of the process by which they are generated.

National Institute of Health (NIH)
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Molecular Genetics A Study Section (MGA)
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Janes, Daniel E
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Schvarzstein, Mara; Pattabiraman, Divya; Libuda, Diana E et al. (2014) DNA helicase HIM-6/BLM both promotes MutS?-dependent crossovers and antagonizes MutS?-independent interhomolog associations during caenorhabditis elegans meiosis. Genetics 198:193-207
Holloway, J Kim; Sun, Xianfei; Yokoo, Rayka et al. (2014) Mammalian CNTD1 is critical for meiotic crossover maturation and deselection of excess precrossover sites. J Cell Biol 205:633-41
Stamper, Ericca L; Rodenbusch, Stacia E; Rosu, Simona et al. (2013) Identification of DSB-1, a protein required for initiation of meiotic recombination in Caenorhabditis elegans, illuminates a crossover assurance checkpoint. PLoS Genet 9:e1003679
Rosu, Simona; Zawadzki, Karl A; Stamper, Ericca L et al. (2013) The C. elegans DSB-2 protein reveals a regulatory network that controls competence for meiotic DSB formation and promotes crossover assurance. PLoS Genet 9:e1003674
Libuda, Diana E; Uzawa, Satoru; Meyer, Barbara J et al. (2013) Meiotic chromosome structures constrain and respond to designation of crossover sites. Nature 502:703-6
Yokoo, Rayka; Zawadzki, Karl A; Nabeshima, Kentaro et al. (2012) COSA-1 reveals robust homeostasis and separable licensing and reinforcement steps governing meiotic crossovers. Cell 149:75-87
Henzel, Jonathan V; Nabeshima, Kentaro; Schvarzstein, Mara et al. (2011) An asymmetric chromosome pair undergoes synaptic adjustment and crossover redistribution during Caenorhabditis elegans meiosis: implications for sex chromosome evolution. Genetics 187:685-99
Rosu, Simona; Libuda, Diana E; Villeneuve, Anne M (2011) Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number. Science 334:1286-9
Schvarzstein, Mara; Wignall, Sarah M; Villeneuve, Anne M (2010) Coordinating cohesion, co-orientation, and congression during meiosis: lessons from holocentric chromosomes. Genes Dev 24:219-28
Bessler, Jessica B; Andersen, Erik C; Villeneuve, Anne M (2010) Differential localization and independent acquisition of the H3K9me2 and H3K9me3 chromatin modifications in the Caenorhabditis elegans adult germ line. PLoS Genet 6:e1000830

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