Sexual reproduction involves the fusion of two sets of chromosomes - one from each parent - to form a new zygote. To avoid doubling their chromosome number with each successive generation, all sexually reproducing organisms must undergo meiosis. This special cell division process gives rise to haploid gametes such as sperm, eggs, and pollen, which contain one complete set of chromosomes. Errors in meiosis are a major cause of human miscarriages, infertility, and mental retardation arising from chromosomal birth defects such as Down syndrome. Studies of meiosis have yielded insights into fundamental cell processes, including DNA repair, chromosome dynamics, and cell cycle regulation. The defining event of meiosis is a reductional cell division in which the two homologous copies of each chromosome are segregated to different daughter cells. To accomplish this separation, each chromosome must first establish a physical connection with its partner through pairing, assembly of the synaptonemal complex, and crossover recombination. We study meiosis in the nematode roundworm Caenorhabditis elegans, which offers major experimental advantages, including outstanding cytology and powerful genetic tools. Recent technical breakthroughs have made it possible to address more detailed questions about meiotic mechanisms in this system. The work proposed here will identify novel meiotic components and investigate how their functions are coordinated to ensure faithful meiotic chromosome segregation. As one entry point to identify meiotic components and regulatory mechanisms, we will build on the knowledge that three conserved serine/threonine kinases, CHK-2, PLK-2, and AIR-2, play essential regulatory roles in meiosis. By identifying direct targets for these kinases and studying the consequences of their phosphorylation in vivo we will illuminate mechanisms by which post-translational modification controls chromosome organization and dynamics. Our other major goal is to investigate the role of the conserved structure known as the synaptonemal complex in regulating the timing and distribution of meiotic recombination events. To accomplish this, we plan to study the dynamic process of synaptonemal complex assembly through in vivo imaging and image analysis, and to define the large-scale changes in chromosome structure that accompany loading of this complex between paired chromosomes. Through these approaches, we will learn how this molecular machine assembles from its component parts to govern the reassortment of genetic traits during sexual reproduction.

Public Health Relevance

The genome of an organism, which encodes its genetic blueprint, is organized into a set of chromosomes that must be replicated and partitioned during every cell division. Sexual reproduction requires a unique cell division process known as meiosis, which leads to the production of sex cells such as eggs and sperm. Errors in meiosis are a major cause of human birth defects, mental retardation and infertility. Our work will investigate how cells execute this process faithfully to transmit genetic information from one generation to the next.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065591-10
Application #
8464137
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Janes, Daniel E
Project Start
2002-04-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$274,945
Indirect Cost
$99,074
Name
University of California Berkeley
Department
Miscellaneous
Type
Organized Research Units
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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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
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