Sunny Kim

Sunny Kim

PhD student, Biochemistry Department

Background:

Sc.B. Biochemistry, Brown University, 2001
Summer intern, Dr. Barry Levin's lab, University of Medicine and Dentistry of New Jersey, 1999
Summer intern, Dr. Rene Hen's lab, Columbia University, 1998

Research:
The repair of double-strand breaks (DSBs) in DNA is critical for maintaining genomic integrity, for unrepaired or improperly repaired lesions can lead to cell death and cancer. DSBs are repaired by two pathways, homologous recombination and nonhomologous end-joining (NHEJ). Homologous recombination occurs conservatively such that there is no nucleotide loss or addition whereas NHEJ can occur conservatively or nonconservatively due to nucleolytic processing prior to ligation. In mammalian cells, NHEJ repairs DSBs induced by ionizing radiation or created during V(D)J recombination, a pathway that generates immunological diversity. Proteins required for NHEJ include Ku, DNA-PKcs, XRCC4, and ligase IV. Ku and DNA-PKcs are the DNA-binding and catalytic subunits of DNA-dependent protein kinase (DNA-PK), which is activated upon binding to free ends of DSBs. This is followed by the binding of XRCC4 and ligase IV, which form a heterotetramer with DNA ligation activity. DNA-PKcs is a 465 kDa serine-threonine protein kinase belonging to the phosphatidylinositol 3-kinase (PI3K) family of lipid and protein kinases. DNA-PKcs has recently been shown to mediate synapsis of DNA ends during DSB repair while its kinase activity is activated by DNA ends. Moreover, the fungal metabolite wortmannin, an inhibitor of PI3 kinases, inhibits NHEJ in cell-free extracts, suggesting that the kinase activity of DNA-PKcs is involved in NHEJ. Potential substrates of DNA-PKcs phosphorylation have been identified through in vitro studies. There is also evidence of autophosphorylation. However, in vivo substrates of DNA-PKcs and the role of its kinase activity in DSB repair remain unclear. Recently, Baumann and West (1998) have developed a cell free system for studying NHEJ that is dependent upon Ku, DNA-PKcs, Xrcc4, and ligase IV, factors that were genetically identified as critical in DSB repair. We will use this system to further pursue the role of DNA-PKcs kinase activity.