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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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 2012

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Cisplatin
DNA Damage
Drug Therapy
Neoplasms
DNA Adducts
DNA-Directed DNA Polymerase
Base Pairing
Catalytic Domain
2'-deoxycytidine 5'-triphosphate
Therapeutics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Ummat, A., Rechkoblit, O., Jain, R., Roy Choudhury, J., Johnson, R. E., Silverstein, T. D., ... 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

Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy. / Ummat, Ajay; Rechkoblit, Olga; Jain, Rinku; Roy Choudhury, Jayati; Johnson, Robert E.; Silverstein, Timothy D.; Buku, Angeliki; Lone, Samer; Prakash, Louise; Prakash, Satya; Aggarwal, Aneel K.

In: Nature Structural and Molecular Biology, Vol. 19, No. 6, 06.2012, p. 628-632.

Research output: Contribution to journalArticle

Ummat, A, Rechkoblit, O, Jain, R, Roy Choudhury, J, Johnson, RE, Silverstein, TD, Buku, A, Lone, S, Prakash, L, Prakash, S & Aggarwal, AK 2012, 'Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy', Nature Structural and Molecular Biology, vol. 19, no. 6, pp. 628-632. https://doi.org/10.1038/nsmb.2295
Ummat, Ajay ; Rechkoblit, Olga ; Jain, Rinku ; Roy Choudhury, Jayati ; Johnson, Robert E. ; Silverstein, Timothy D. ; Buku, Angeliki ; Lone, Samer ; Prakash, Louise ; Prakash, Satya ; Aggarwal, Aneel K. / Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy. In: Nature Structural and Molecular Biology. 2012 ; Vol. 19, No. 6. pp. 628-632.
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