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 regulate and execute meiotic crossing over and chiasma 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 regulation mechanisms have been shown to operate. The proposed work will exploit recent advances that allow 1) cytological visualization of crossover-triggered changes in chromosome state and changes in the mode of DSBR, and 2) manipulation of the timing of meiotic prophase progression and the timing and location of DSB formation. We will investigate the mechanisms by which chromatin-associated protein HIM-17 functions in promoting initiation of meiotic recombination, chromatin modification and regulation of meiotic entry. We will investigate the mechanisms and regulation of meiotic recombination using methods designed to manipulate the timing and location of DSB formation and the timing of meiotic prophase progression. We will use a large battery of cytological and genetic functional assays to investigate the roles of newly-identified components of the crossover recombination machinery. Finally, we will investigate the role of HIM- 6/BLM in the formation of functional chiasmata. In addition to elucidating mechanisms important for chromosome inheritance during meiosis, this latter aim should yield insights regarding the etiology of genomic instability in patients with Bloom Syndrome, an inherited disorder causing predisposition to all types of cancer.

Public Health Relevance

The proposed research will increase our understanding of the mechanisms that maintain chromosome integrity and ensure faithful inheritance of chromosomes. The work is highly relevant to human health, as errors in chromosome inheritance are one of the leading causes of miscarriages and birth defects and are also a major factor contributing to the development and progression of cancer. One component of the research plan will shed light on the mechanisms that lead to chromosome instability in patients with Bloom Syndrome, an inherited disorder causing predisposition to all types of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067268-07
Application #
7782765
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Hagan, Ann A
Project Start
2003-06-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$310,098
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Jagut, Marlène; Hamminger, Patricia; Woglar, Alexander et al. (2016) Separable Roles for a Caenorhabditis elegans RMI1 Homolog in Promoting and Antagonizing Meiotic Crossovers Ensure Faithful Chromosome Inheritance. PLoS Biol 14:e1002412
Roelens, Baptiste; Schvarzstein, Mara; Villeneuve, Anne M (2015) Manipulation of Karyotype in Caenorhabditis elegans Reveals Multiple Inputs Driving Pairwise Chromosome Synapsis During Meiosis. Genetics 201:1363-79
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
Rosu, Simona; Libuda, Diana E; Villeneuve, Anne M (2011) Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number. Science 334:1286-9
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

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