Biological Consequences and Repair of Alkylated Thymidine Lesions

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Environmental exposure and endogenous metabolism both give rise to the alkylation of DNA, and DNA alkylation represents the major mechanism of action for a number of commonly prescribed cancer chemotherapeutic agents. Thus, assessing how alkylated DNA lesions compromise the flow of genetic information by altering the efficiency and fidelity of DNA replication and transcription and how these lesions are repaired will provide important knowledge for understanding the implications of DNA alkylation in the etiology for developing human diseases. Such knowledge will also form the basis for developing better strategies for cancer chemotherapy. The emphasis of this application is placed on a group of alkylated thymidine lesions which have been shown to persist in mammalian tissues or have been detected at substantially elevated levels in lymphocyte samples of humans exposed to cigarette smoke. We will employ an innovative and multi- pronged approach, including synthetic organic chemistry, mass spectrometry-based bioanalytical chemistry, and molecular biology to achieve a molecular-level understanding about how the under-investigated group of alkylated thymidine lesions impede DNA replication and transcription in cells, and induce mutations in these processes. We will also assess the implications of nucleotide excision repair and base excision repair pathways in the repair of these lesions in cells. The outcome of the proposed research will bring our understanding of this largely overlooked group of alkylated DNA lesions to a significantly higher level.