Meiotic damage-detection checkpoints monitor meiotic progression and ensure the integrity of the genome of the next generation by sensing DNA damage and halting progression until that damage is repaired. If a chromosome aberration, genetic mutation, or external chemical assault leads to unrepaired damage, the appropriate checkpoint shunts the spermatocyte into an apoptotic pathway and, if a sufficient number of spermatocytes are affected, sterility results. While mitotic checkpoints and their controls are reasonably well characterized, the same can not be said of meiotic checkpoints. This proposal addresses some of the unanswered questions in our knowledge of DNA damage-detection checkpoints in mammalian spermatocytes. These essential questions include: How many meiotic checkpoints are there? Where are they located in meiosis? What events do they monitor and what triggers a checkpoint arrest? What meiotic checkpoint proteins have been """"""""borrowed"""""""" from the mitotic cycle and are they being used in the same or different ways in meiosis? What are the regulators of the cascades that constitute the meiotic checkpoint pathways? To address these questions we will use a combination of 1) immunohistochemistry (antibody localization) on microspread spermatocytes, 2) histopathological evaluation of testis sections, 3) evaluation of mice with genetic or extrinsic defects, including various chromosomal aberrations, targeted disruption of genes necessary for progression of meiotic events or chemical disruption of meiosis. Our goal is to identify the meiotic checkpoints and their protein components, to elucidate the pathways in which they function, and to determine the activities they monitor and what triggers a checkpoint arrest. Our results will lead to a better understanding of some of the underlying causes of male sterility and could also lead to new insights into development of a male contraceptive.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039384-03
Application #
6536197
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Tasca, Richard J
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$294,300
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Saitta, Sulagna C; Harris, Stacy E; Gaeth, Ann P et al. (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet 13:417-28
Hamer, Geert; Kal, Henk B; Westphal, Christoph H et al. (2004) Ataxia telangiectasia mutated expression and activation in the testis. Biol Reprod 70:1206-12
Lynn, Audrey; Ashley, Terry; Hassold, Terry (2004) Variation in human meiotic recombination. Annu Rev Genomics Hum Genet 5:317-49
Ashley, T; Westphal, C; Plug-de Maggio, A et al. (2004) The mammalian mid-pachytene checkpoint: meiotic arrest in spermatocytes with a mutation in Atm alone or in combination with a Trp53 (p53) or Cdkn1a (p21/cip1) mutation. Cytogenet Genome Res 107:256-62
Suphapeetiporn, Kanya; Greally, John M; Walpita, Deepika et al. (2002) MEN1 tumor-suppressor protein localizes to telomeres during meiosis. Genes Chromosomes Cancer 35:81-5