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

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 ? (hPol ?). Here, we report crystal structures of hPol ? 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 ? is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol ? differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol ? 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 ? 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 ? is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance.

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC3358888 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature