Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy

Abstract

A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase η (Polη) is a key polymerase that allows cancer cells to cope with cisplatin–DNA adducts formed during chemotherapy. We present here a structure of human Polη inserting dCTP opposite a cisplatin intrastrand cross-link (PtGpG). We show that specificity of human Polη for PtGpG derives from an active site that is open to permit Watson-Crick geometry of the nascent PtGpG•dCTP base pair and to accommodate the lesion without steric hindrance. The specificity is augmented by residues Gln38 and Ser62 that interact with PtGpG, and Arg61 that interacts with incoming dCTP. Collectively, the structure provides a basis for understanding how Polη in human cells can tolerate DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.