Protein-Protein Interactions in DNA Repair Pathways

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DESCRIPTION (provided by applicant): The chemical structure of DNA is continuously altered in the reactive cellular environment. Damaged DNA often introduces mutations in the genome that have potentially cytotoxic or dysfunctional effects. Therefore, organisms have developed repair pathways to correct various types of DNA damage. The importance in understanding these repair pathways is underscored by the fact that genetic mutations give rise to disease and cancer. Base excision repair (BER) is the primary means for correcting DNA damage done by oxidizing and alkylating agents. The BER pathway involves a series of enzymes that excises damaged DNA bases, incorporates correct DNA bases, and returns the DNA structure to its natural form. The enzymes in this pathway act in a concerted manner, passing fragile DNA intermediates from one step to the next. This study focuses on the last steps of BER: polymerase gap-filling and ligation of nicked DNA strands. The specific aims are to 1) determine crystal structures of human ligase I (Lig1), or catalytically active fragments of Lig1, with and without DNA intermediates and 2) identify and crystallize a stable complex of Lig1 and polymerase a (Pola) that demonstrates their biological interaction and solve the crystal structure of the complex.