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.
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.
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