Our objective is to understand how homologous recombination and telomere organization contribute to the juxtaposition of homologous chromosomes in meiosis. These processes are essential to proper chromosome segregation at anaphase I. Defects in these processes can lead to aneuploid gametes, which contribute to birth defects in humans. Mechanisms underlying these processes (double-strand break repair, telomere integrity and chromosome organization) contribute directly to the genesis of cancer cells. How homologs pair is a major unanswered question in the study of meiosis. We propose experiments using budding yeast to address two central questions: i) to what extent do base-pairing interactions contribute to the ability of homologous chromosomes to find one another? And ii) what defines the mechanistic link between dynamic organization of telomeres, recombination, and close, stable homolog juxtaposition (CSHJ). Our hypothesis is that a specific mechanistic step of recombination depends in part on telomere integrity, position or motion. This step is the stabilization of strand-invasion intermediates. A telomere-bound protein, Ndj1, is involved in linking telomere function to chromosome recombination and segregation in meiosis. We propose roles for chromatin structure and DNA damage checkpoint proteins in achieving CSHJ. 1. We will determine the mechanistic step(s) in meiotic recombination that lead to CSHJ. We will use a new quantitative assay that reports on the relative spatial position or accessibility of two chromosomal loci. 2. We will determine the specific features of meiotic telomere reorganization that impact meiotic recombination. We will explore the potential roles of spatial constraint, chromosome motion and a possible direct role in recombination by Ndj1 or other known telomere-bound proteins. 3. We will identify genes by mutation that act in concert with Ndj1 to promote the stabilization of strand invasion intermediates. Genome-wide and candidate gene approaches will be taken. Lay description: Pregnancy loss and birth defects result from embryos having abnormal chromosome numbers (e.g. trisomy 21 or Downs syndrome). This research focuses on understanding how chromosomes are properly distributed to sperm and egg cells. Our findings will impact health of future generations. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM075119-03
Application #
7476512
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Portnoy, Matthew
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$272,849
Indirect Cost
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Chu, Daniel B; Burgess, Sean M (2016) A Computational Approach to Estimating Nondisjunction Frequency in Saccharomyces cerevisiae. G3 (Bethesda) 6:669-82
Schuster, Kevin; Leeke, Bryony; Meier, Michael et al. (2015) A neural crest origin for cohesinopathy heart defects. Hum Mol Genet 24:7005-16
Lui, Doris Y; Cahoon, Cori K; Burgess, Sean M (2013) Multiple opposing constraints govern chromosome interactions during meiosis. PLoS Genet 9:e1003197
Ho, Hsuan-Chung; Burgess, Sean M (2011) Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis. PLoS Genet 7:e1002351
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Lui, Doris; Burgess, Sean M (2009) Measurement of spatial proximity and accessibility of chromosomal loci in Saccharomyces cerevisiae using Cre/loxP site-specific recombination. Methods Mol Biol 557:55-63
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