1. Bypass of DNA Lesions Generated During Anticancer Treatment with Cisplatin by DNA Polymerase η.
- Author
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Alt, Aaron, Lammens, Katja, Chiocchini, Claudia, Lammens, Alfred, Pieck, J. Carsten, Kuch, David, Hopfner, Karl-Peter, and Carell, Thomas
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ANTINEOPLASTIC agents , *PRECANCEROUS conditions , *ULTRAVIOLET radiation , *DRUG therapy , *DNA polymerases , *TUMORS - Abstract
DNA polymerase η (Pot η) is a eukaryotic lesion bypass polymerase that helps organisms to survive exposure to ultraviolet (UV) radiation, and tumor cells to gain resistance against dsplatin-based chemotherapy. It allows cells to replicate across cross-link lesions such as 1,2-d(GpG) cisptatin adducts (Pt-GG) and UV-induced ds-syn thymine dimers. We present structural and biochemical analysis of how Pot η copies Pt-GG-containing DNA. The damaged DNA is bound in an open DNA binding rim. Nucleotidyl transfer requires the DNA to rotate into an active conformation, driven by hydrogen bonding of the temptating base to the dNTP. For the 3′dG of the Pt-GG, this step is accomplished by a Watson-Crick base pair to dCTP and is biochemically efficient and accurate. In contrast, bypass of the 5′dG of the Pt-GG is less efficient and promiscuous for dCTP and dATP as a result of the presence of the rigid Pt cross-link. Our analysis reveals the set of structural features that enable Pot η to replicate across strongly distorting DNA lesions. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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