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PATRICK SUNG

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 the 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.

HR is catalyzed by genes of the RAD52 epistasis group. In addition to DNA repair, these genes also promote the linkage of homologous chromosomes to ensure their proper disjunction in meiosis I and are involved in the removal of interstrand DNA crosslinks. Several cancer-prone genetic diseases, including Bloom's syndrome and Fanconi anemia, are associated with HR dysfunction or deficiency. Furthermore, HR impairment is likely the underlying cause of breast, ovarian, and other cancers in individuals who harbor mutations in the BRCA1 and BRCA2 genes. We showed in 1994 that the 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 HR-dependent processes. This finding marked the beginning of studies on HR enzymology in eukaryotic organisms and has created a much-needed experimental framework for deciphering the mechanism of HR. Capitalizing on our initial success on Rad51, we have been making steady progress toward elucidating the biochemical functions of other members of the RAD52 group and have also begun to address the role of the BRCA2 and BLM tumor suppressors in HR reactions. We employ a combination of biochemical, biophysical, and genetic approaches in our various endeavors.

Selected Publications
Krejci, L., Van Komen, S., Li, Y., Villemain,J., Reddy, M. S., Klein, H., Ellenberger, T. and Sung, P. Srs2 helicase disrupts the Rad51 presynaptic filament. Nature, 423, 305-309 (2003)

Sehorn, M.G., Sigurdsson, S., Bussen, W., Unger, V. M. and Sung, P. The human meiotic recombinase Dmc1 promotes ATP-dependent homologous DNA strand exchange. Nature 429, 433-437 (2004)

San Filippo, J., Chi, P., Sehorn, M.G., Etchin, J., Krejci, L, and Sung, P. Sung. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J. Biol. Chem. 281, 11649-11657 (2006)

Wiese, C., Dray, E., Groesser, T., San Filippo, J., Shi, I., Collins, D. W., Tsai, M. S., Williams, G. J., Rydberg, B., Sung, P. and Schild, D.  Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement.  Mol. Cell. 28, 482-490 (2007)

Busygina, V., Sehorn, M. G., Chi, I. Y., Tsubouchi, H., Roeder, G. S. and Sung, P.  Hed1 regulates Rad51-mediated recombination via a novel mechanism.  Genes Dev. 22, 786-795 (2008)

Last Updated 04-14-08