The long-range goal of the proposed research is to understand the underlying principles governing translesion synthesis past radiation- induced DNA damages. Translesion synthesis is the process whereby a DNA polymerase replicates past an unrepaired lesion; if an incorrect base is inserted, a mutation is fixed and the oncogenic process can be initiated. With DNA lesions that normally block DNA synthesis, two types of translesion synthesis reactions can be described: read through during replication and restart after dissociation of the DNA polymerase from the damage site. The focus of the proposed research is to delineate the molecular events that take place when a replication fork encounters an unrepaired blocking lesion and the factors that influence the restart reaction at a blocked primer terminus. The goals will be accomplished by a combination of enzymological and biological studies designed to elucidate DNA polymerase interactions with templates containing a unique lesion in specific sequence contexts. Emphasis will be on defining the structural and enzymatic parameters that influence bypass of radiation- induced base damages, since lesion bypass is required for mutation fixation and the initiation of carcinogenesis. These studies should provide important insights for recognition and analysis of putative hotspots for point mutations in oncogenes and tumor suppressor genes that have been implicated in the etiology of breast and other forms of human cancer.
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