期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 20, 页码 9321-9336出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00596
关键词
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资金
- UCHC startup funds
- Connecticut Institute of Clinical and Translational Science (CICATS) pilot
- NIH/NCI [CA190617]
- American Cancer Society [RSG-13-131-01]
- NSF [1515808]
- University of Connecticut Research Foundation
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1515808, 1615866] Funding Source: National Science Foundation
Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.
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