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

Ajay Ummat, Olga Rechkoblit, Rinku Jain, Jayati Roy Choudhury, Robert E. Johnson, Timothy D. Silverstein, Angeliki Buku, Samer Lone, Louise Prakash, Satya Prakash, Aneel K. Aggarwal

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57 Scopus citations

Abstract

A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase η (Pol-η) is a crucial polymerase that allows cancer cells to cope with the cisplating-DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-η inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-η 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. This specificity is augmented by the residues Gln38 and Ser62, which interact with PtGpG, and Arg61, which interacts with the incoming dCTP. Collectively, the structure provides a basis for understanding how Pol-η in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.

Original languageEnglish (US)
Pages (from-to)628-632
Number of pages5
JournalNature Structural and Molecular Biology
Volume19
Issue number6
DOIs
StatePublished - Jun 1 2012

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Ummat, A., Rechkoblit, O., Jain, R., Roy Choudhury, J., Johnson, R. E., Silverstein, T. D., Buku, A., Lone, S., Prakash, L., Prakash, S., & Aggarwal, A. K. (2012). Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy. Nature Structural and Molecular Biology, 19(6), 628-632. https://doi.org/10.1038/nsmb.2295