Our goal is to understand both mammalian meiotic recombination and the checkpoints that monitor it. Recombination generates physical connections between homologous chromosomes that are essential for accurate segregation. If recombination is altered, chromosome segregation is affected, and gamete aneuploidy results. The molecular mechanisms of recombination and the processes that protect against recombination errors are not well understood. Mouse is ideal for these studies because of extensive conservation of relevant molecular processes with humans.
Specific aims are to: 1. Characterize crossover homeostasis in mouse. In yeast, crossover numbers are maintained even when DSB frequencies are decreased (""""""""crossover homeostasis""""""""). The same process may operate in mouse. This hypothesis will be tested by cytological and molecular analysis of recombination in male and female animals with reduced dosage of Spo11, the gene encoding the protein that initiates recombination. 2. Define the roles of ATM in meiotic recombination. The checkpoint kinase ATM is required for repair of meiotic DMA breaks and for crossover control. Behaviors of recombination proteins and structures of recombination products will be determined in mice lacking ATM. 3. Define the functions of Spo11 splicing isoforms. Multiple splice variants of mouse and human Spo11 have been described. The functions of the encoded proteins are not known. This issue will be addressed through characterization of mice carrying transgenes or targeted mutations that express individual isoforms. 4. To determine the role of TRIP13 (PCH2) in monitoring chromosome synapsis defects. Recent studies in yeast and nematode demonstrated the existence of a chromosome synapsis checkpoint that is distinct from the recombination checkpoint. We will test whether a mouse homolog of the synapsis checkpoint protein PCH2 functions in a similar pathway in mammalian meiosis. Relevance: Abnormal chromosome numbers in eggs or sperm cause developmental disabilities or spontaneous abortion. These abnormalities often arise because of improper separation of chromosomes caused by defects in meiotic homologous recombination. This project will address fundamental questions about how mammals control meiotic recombination and respond when there are problems.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Taymans, Susan
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Pacheco, Sarai; Marcet-Ortega, Marina; Lange, Julian et al. (2015) The ATM signaling cascade promotes recombination-dependent pachytene arrest in mouse spermatocytes. PLoS Genet 11:e1005017
Ontoso, David; Kauppi, Liisa; Keeney, Scott et al. (2014) Dynamics of DOT1L localization and H3K79 methylation during meiotic prophase I in mouse spermatocytes. Chromosoma 123:147-64
Kauppi, Liisa; Barchi, Marco; Lange, Julian et al. (2013) Numerical constraints and feedback control of double-strand breaks in mouse meiosis. Genes Dev 27:873-86
Dowdle, James A; Mehta, Monika; Kass, Elizabeth M et al. (2013) Mouse BAZ1A (ACF1) is dispensable for double-strand break repair but is essential for averting improper gene expression during spermatogenesis. PLoS Genet 9:e1003945
Kauppi, Liisa; Jasin, Maria; Keeney, Scott (2013) How much is enough? Control of DNA double-strand break numbers in mouse meiosis. Cell Cycle 12:2719-20
Cole, Francesca; Kauppi, Liisa; Lange, Julian et al. (2012) Homeostatic control of recombination is implemented progressively in mouse meiosis. Nat Cell Biol 14:424-30
Kauppi, Liisa; Jasin, Maria; Keeney, Scott (2012) The tricky path to recombining X and Y chromosomes in meiosis. Ann N Y Acad Sci 1267:18-23
Cole, Francesca; Keeney, Scott; Jasin, Maria (2012) Preaching about the converted: how meiotic gene conversion influences genomic diversity. Ann N Y Acad Sci 1267:95-102
Shakya, Reena; Reid, Latarsha J; Reczek, Colleen R et al. (2011) BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334:525-8
Cole, Francesca; Jasin, Maria (2011) Isolation of meiotic recombinants from mouse sperm. Methods Mol Biol 745:251-82

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