Our long term goal is to elucidate how genetic recombination contributes to the faithful inheritance of chromosomes during meiosis, the specialized cell division program by which diploid organisms generate haploid gametes. Chromosome inheritance during meiosis relies on the formation of double-strand DNA breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). Failure to form COs leads to chromosome missegregation and consequent aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Because the DSBs that serve as the initiating events of meiotic recombination pose a danger to genome integrity, the success of genome inheritance during meiosis requires cells to maintain a balance between the beneficial effects of COs and the potential harmful consequences of the process by which they are generated. Our goal is to understand the mechanisms that operate during meiosis to achieve this crucial balance. We are approaching this problem using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining sophisticated cytological, genetic and genomic approaches in a single experimental system, and in which the events under study are particularly accessible and robust. The proposed work will exploit recent advances that provide the means to mark the sites of nascent CO events in live and fixed germ cells, to quantify the strength of CO interference, to manipulate the genome efficiently both at the DNA level and at the level of organismal ploidy, to visualize and reveal previously inaccessible organizational features of the DNA repair complexes assembled at recombination sites, and to obtain high-quality genome-wide information on chromatin organization from small numbers of cells. One goal is to elucidate the architecture and organization of DNA repair complexes at in vivo sites of meiotic recombination, with the objective of deducing and reconcilng relationships between the activities of individual recombination proteins/complexes and the in vivo functions of the collective CO recombination machinery. Another goal is to understand the mechanisms that promote and limit formation of meiotic COs, both at the level of designating recombination sites for a CO or non-CO fate and at the level of enforcing reliable execution of these fates. Finally, we will investigate processes that promote the formation of sufficient DSBs to guarantee CO formation and that efficiently channel these DSBs into homologous-recombination based repair pathways and away from error- prone mutagenic repair pathways.
The proposed research will increase our understanding of the basic mechanisms that promote and ensure the 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. Several aspects of our program address how DNA damage is recognized and repaired appropriately, which is important for maintaining intact chromosomes and inhibiting cancer progression.
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