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(1) Pre-Steady State Kinetic Studies of DNA Lesion Bypass Polymerases DNA lesions often block DNA replication, so cells possess specific, often error-prone, DNA polymerases to bypass such lesions and promote replication of damaged DNA. More than 220 DNA lesion bypass polymerases have been discovered in the last two years. These polymerases which share sequence similarity and catalyze DNA polymerization with low fidelity and poor processivity are classified into a new Family, the Y-family. Human polymerases eta (h), iota (i), and zeta (z)are examples of those repairing enzymes. Polymerase (Pol) h, encoded by hRAD30A, bypasses cis-syn thymine-thymine dimmer efficiently and accurately. Mutations in hRAD30A inactivate hPol h and lead to UV-induced mutagenesis and skin cancer. My laboratory is using the pre-steady state kinetic methods to decipher the detailed mechanisms of incorporations of correct and incorrect nucleotides opposite undamaged or damaged DNA templates by Dpo4, a thermostable polymerase from Sulfolobus solfataricus strain P2. We are collaborating with the group of Hong Ling at the University of Western Ontario, Canada, to crystallize the binary and ternary complexes of Dpo4. We are also collaborating with the group of Dr. Dongping Zhong to study the dynamic interactions among Dpo4, DNA, and an incoming nucleotide using the femtosecond-resolved fluorescence up-conversion techniques. Our collaborative studies will establish a general kinetic, thermodynamic, and structural mechanism for DNA translesion synthesis. More importantly, a better understanding of the Y-family polymerases based on our results will facilitate the understanding of cancer formation and the development of anti-cancer drugs. (1) Pre-Steady State Kinetic Studies of DNA Lesion Bypass Polymerases (2) Kinetic and Protein-Protein Interaction Studies of Human DNA Polymerases lambda, µ and TdT (4) Design and Synthesis of Novel Nucleoside Analog Inhibitors (5) Developing Anti-HCV Peptide-Based Inhibitors (6) Effects of HCV Protease NS3/4A on Human
Kinases Involved in Immune Response |
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