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Mutagenesis Advance Access published online on April 16, 2009
Mutagenesis, doi:10.1093/mutage/gep011
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© The Author 2009. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for noncommercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

The Xpc gene markedly affects cell survival in mouse bone marrow

Joshua L. Fischer, M.A. Suresh Kumar, Travis W. Day1, Tabitha M. Hardy, Shari Hamilton2, Cynthia Besch-Williford2, Ahmad R. Safa1, Karen E. Pollok3 and Martin L. Smith*

Department of Microbiology and Walther Oncology Center, Indiana University Simon Cancer Center and Walther Cancer Institute 1Department of Pharmacology, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA 2Department of Veterinary Pathology and Research Animal Diagnostic Laboratory, University of Missouri-Columbia, Columbia, MO 65211, USA 3Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc–/– mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc–/– and strain-matched wild-type mice. Using several independent methods, Xpc–/– bone marrow was ~10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc–/– mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.

* To whom correspondence should be addressed. Indiana University Simon Cancer Center, 1044 West Walnut Street, Room 155, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Tel: +1-317-278-0225; Fax: +1-317-278-3331; Email: marlsmit{at}iupui.edu

Received on January 27, 2009; revised on March 6, 2009; accepted on March 21, 2009.


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