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Department of Molecular Biophysics and Biochemistry
Yale University

333 Cedar Street, PO Box 208024
New Haven, CT 06520-8024
Phone Number (203) 785-4569

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Homologous Recombination and DNA Double-strand Break Repair in Eukaryotes

Endogenous free radicals and environmental agents such as ionizing radiation induce DNA double-strand breaks. The repair of these breaks is crucial for the maintenance of genome stability. Two distinct pathways help eliminate DNA double-strand breaks. In homologous recombination (HR), the repair of a broken DNA molecule requires an intact homologous duplex to direct the process. Alternatively, a pathway known as non-homologous DNA end joining (NHEJ) simply rejoins the ends of the broken DNA molecule. Our research efforts focus on delineating the mechanism of homology-directed repair of DNA double-strand breaks in the yeast Saccharomyces cerevisiae and humans.

Repair by homologous recombination (HR):
The recombinational repair of DNA double-strand breaks is mediated by a group of genes called the RAD52 epistasis group. In mammals, the efficiency of recombinational DNA repair is modulated by the tumor suppressors BRCA1 and BRCA2, providing compelling evidence that this repair pathway functions to suppress cancer formation. Importantly, recombinational DNA repair is also required for the removal of interstrand DNA crosslinks induced by bifunctional crosslinking agents, which are commonly used to treat various malignancies. Our studies have shown that Rad51 protein, a key member of the RAD52 group, is the recombinase enzyme that mediates the "homologous DNA pairing and strand exchange" reaction central to all recombination-dependent processes, including the repair of DNA double-strand breaks. This finding marked the beginning of studies on recombination enzymology in eukaryotic organisms and has created a much-needed experimental framework for dissecting the role of the other RAD52 group members in recombination reactions. Capitalizing on our initial work with Rad51, we have since been making progress toward elucidating the biochemical functions of other members of the RAD52 group, and our work has begun to address the role of chromatin in recombination reactions as well. Our studies feature a combination of biochemical, biophysical, and genetic approaches.

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