Homologous recombination during meiosis is essential for genome integrity in the germ line, but is also a powerful determinant of genome diversity, evolution, and (when mistakes occur) instability. Meiotic recombination is initiated by double-strand breaks (DSBs) made by the Spo11 protein. DSBs are important for successful meiosis, but are also dangerous lesions that can mutate or kill, so cells ensure that DSBs are made only at the right times, places, and amounts. DSB processing and recombination are also controlled to maximize repair efficiency and minimize risks of deleterious outcomes. A fundamental problem in reproductive biology and genome integrity is to understand the molecular mechanisms of DSB formation and of the processes that regulate DSBs and recombination. Mouse and the budding yeast S. cerevisiae will be used to explore these critical aspects of chromosome biology. Specific areas of inquiry include the following: * Recent work uncovered a complex network of circuits that control the number, timing, and distribution of DSBs. One important circuit involves DSB-dependent activation of the DNA damage-response kinase ATM, which feeds back to inhibit additional break formation. A second, distinct feedback circuit suppresses DSB formation in places where homologous chromosomes have successfully engaged one another. The outlines of this network are understood in only broad strokes; an important challenge now is to define detailed mechanisms and interactions between different regulatory circuits. The nonrandom distribution of DSBs has important consequences for heritability and genome evolution, but factors shaping the DSB landscape remain poorly understood. This lack of essential information will be ad- dressed using powerful methods that were recently developed to map DSB distributions genome-wide at nucleotide resolution. DSB ends must be processed by exonucleases to allow recombination, but little is known about the mechanism. A novel whole-genome assay for DSB resection has been devised that will permit unprecedented exploration of this important, but understudied, aspect of recombination. Recombination between dispersed copies of repetitive sequences is a potent source of germ line mutations. Important challenges now are to understand the mechanisms of this non-allelic homologous recombination and to understand the pathways cells exploit to minimize this risk. Sex chromosome segregation is particularly fraught in mammalian male meiosis because the X and Y chromosomes share only a small region of homology (the pseudoautosomal region, or PAR) within which re- combination must occur. Defects in PAR recombination cause sterility or sex chromosome missegregation. Key questions will be addressed concerning the properties of the PAR and of spermatocytes that ensure the fidelity of sex chromosome segregation.

Public Health Relevance

Abnormal chromosome numbers in eggs or sperm cause developmental disabilities or miscarriage. These abnormalities often arise because of improper separation of chromosomes caused by defects in meiotic homologous recombination. This project will address fundamental questions about the mechanism and control of recombination and thus is of direct relevance to human reproductive health and disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Gindhart, Joseph G
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Widger, Alexander; Mahadevaiah, Shantha K; Lange, Julian et al. (2018) ATR is a multifunctional regulator of male mouse meiosis. Nat Commun 9:2621
Pacheco, Sarai; Maldonado-Linares, Andros; Marcet-Ortega, Marina et al. (2018) ATR is required to complete meiotic recombination in mice. Nat Commun 9:2622
Mimitou, Eleni P; Keeney, Scott (2018) S1-seq Assay for Mapping Processed DNA Ends. Methods Enzymol 601:309-330
Lukaszewicz, Agnieszka; Lange, Julian; Keeney, Scott et al. (2018) Control of meiotic double-strand-break formation by ATM: local and global views. Cell Cycle 17:1155-1172
Abreu, Carla M; Prakash, Rohit; Romanienko, Peter J et al. (2018) Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination. Nat Commun 9:3961
Yamada, Shintaro; Kim, Seoyoung; Tischfield, Sam E et al. (2017) Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice. Cell Cycle 16:1870-1884
Kniewel, Ryan; Murakami, Hajime; Liu, Yan et al. (2017) Histone H3 Threonine 11 Phosphorylation Is Catalyzed Directly by the Meiosis-Specific Kinase Mek1 and Provides a Molecular Readout of Mek1 Activity in Vivo. Genetics 207:1313-1333
Mimitou, Eleni P; Yamada, Shintaro; Keeney, Scott (2017) A global view of meiotic double-strand break end resection. Science 355:40-45
Lam, Isabel; Mohibullah, Neeman; Keeney, Scott (2017) Sequencing Spo11 Oligonucleotides for Mapping Meiotic DNA Double-Strand Breaks in Yeast. Methods Mol Biol 1471:51-98
Mohibullah, Neeman; Keeney, Scott (2017) Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1. Genome Res 27:278-288

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