Patrick Sung, PhD
Professor, Department of Molecular Biophysics & Biochemistry and Therapeutic Radiology
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patrick.sung@yale.edu Phone: 203.785.4553 Appt Phone: Fax: 203.785.6037 Yale University School of Medicine Department of Molecular Biophysics & Biochemistry SHM 130A New Haven, Connecticut 06520 |
Degrees/Education:
B.Sc., University of Liverpool (1981)
D. Phil., Oxford University (1985)
Faculty Appointments:
Postdoctoral Fellow, University of Rochester (1985-93)
Assistant Professor, University of Texas Medical Branch at Galveston (1993-97)
Associate/Full Professor, University of Texas Health Science Center at San Antonio (1997-2003)
Professor, Yale University School of Medicine, Department of Molecular Biophysics & Biochemistry and Therapeutic Radiology
Research Interests:
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, 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 mechanisms of these two DNA repair pathway.
Repair by homologous recombination
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 tumour 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. In 1994, we identified the yeast Rad51 protein, a key member of the RAD52 group, as the recombinase 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 the recombination reaction. Capitalizing on our initial work with RAD51, we have since been making considerable progress toward elucidating the biochemical functions of other members of the RAD52 group, including Rad52, Rad54, Rad55, Rad57, Rad59, and Rdh54/Tid1. Recent studies have begun ot address the role of chromatin in recombination reactions as well.
Repair by DNA end-joining
Another way to repair DNA double-strand breaks is by joining of the ends of the breaks. In addition to DNA ligase IV (Dn14 in yeast), genetic and biochemical studies in yeast and mammalian cells have identified a large number of proteins as essential components of the end-joining process. Using purified yeast Dn14/Lif1complex , Rad50/Mre11/Xrs2 complex, and Hdf1/Jdf2 complex, we have recently succeeded in reconstituting the end-joining reaction in vitro. The central tenet of most NHEJ models incorporates an end-bridging factor that juxtaposes DNA ends and provides the scaffold upon which the NHEJ machinery is assembled. Our work has identified the Rad50/Mre11/Xrs2 complex as an end-bridging factor that interacts with and specifically stimulates end-joining by Dn14/Lif1. Furthermore, we have demonstrated that DNA joining mediated by the combination of Dn14/Lif1 and Rad50/Mre11/Xrs2 is further stimulated by Hdf1/Hdf2 under physiological ionic conditions. The reconstituted end-joining system should allow us to decipher the mechanistic intricacies of NHEJ.
