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Proc Natl Acad Sci U S A. 2012 May 8;109(19):7269-74. doi: 10.1073/pnas.1202681109. Epub 2012 Apr 23.

Structural basis of human DNA polymerase η-mediated chemoresistance to cisplatin.

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1
Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029, China.

Abstract

Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase η (hPol η). Here, we report crystal structures of hPol η complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol η is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol η differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol η undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol η is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol η is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.

PMID:
22529383
PMCID:
PMC3358888
DOI:
10.1073/pnas.1202681109
[Indexed for MEDLINE]
Free PMC Article
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