Ionizing radiation, mutagenic chemicals, and replication of a damaged DNA template can induce DNA double-stranded breaks. If not handled properly, these breaks often lead to gross chromosome rearrangements. Homologous recombination helps eliminate DNA strand breaks in eukaryotes and is needed for tumor suppression in humans. In the homologous repair of a double-stranded break, the ends of the break are subject to exonucleolytic processing to yield 3'single-stranded DNA tails. Nucleation of various recombination factors onto these DNA tails renders them recombinogenic, leading to a search for the chromosomal homolog and the stable pairing of the DNA tails with the homolog to form a DNA joint called """"""""D-loop"""""""". In the later stages, DNA synthesis occurs, followed by the resolution of DNA intermediates to yield mature recombinants and restore the integrity of the injured chromosome. The evolutionarily conserved genes of the RAD52 epistasis group, of which RAD54 and RDH54 are key members, mediate homologous recombination and DNA strand break repair by recombination. Rad54 and Rdh45 are members of the Swi2/Snf2 super-family of DNA motor proteins. Studies to date have unveiled DNA translocase and chromatin remodeling activities in these two recombination factors and have provided an experimental framework for examining the functional interactions of these factors with the Rad51 and Dmc1 recombinases. Herein, we outline strategies for the continuing dissection of the multi-faceted role of Rad54 and Rdh54 in recombination and DNA repair reactions, for the identification and molecular characterization of Rad54 and Rdh54 protein complexes, and for the elucidation of a novel mechanism of recombination regulation that targets the Rad51/Rad54 axis. These planned studies should continue to yield insights into the mechanism of recombination pathways in eukaryotic cells.
Our studies focus on the mechanism by which eukaryotic cells eliminate pre-cancerous lesions, such as DNA double-stranded breaks that are induced by ionizing radiation and chemicals, from chromosomes. Importantly, defective chromosome damage repair is the underlying cause of several cancer-prone diseases (e.g. Bloom's syndrome, Nijmegen breakage syndrome, and Fanconi anemia) and can pre-dispose affected individuals to a variety of cancers, including breast, ovarian, and pancreatic cancers. For these reasons, the studies outlined in the renewal application have direct relevance to cancer biology and public health.
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