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

Authors :
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
Source :
Nature Structural & Molecular Biology. Jun2012, Vol. 19 Issue 6, p628-632. 5p. 3 Diagrams, 1 Chart.
Publication Year :
2012

Abstract

A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase ? (Pol-?) is a crucial polymerase that allows cancer cells to cope with the cisplatin-DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-? inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-? 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-? in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15459993
Volume :
19
Issue :
6
Database :
Academic Search Index
Journal :
Nature Structural & Molecular Biology
Publication Type :
Academic Journal
Accession number :
76349330
Full Text :
https://doi.org/10.1038/nsmb.2295