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