Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes

Joost P.M. Melis, Susan W.P. Wijnhoven, Rudolf B. Beems, Marianne Roodbergen, Jolanda Van Den Berg, Hojin Moon, Errol Friedberg, Gijsbertus T.J. Van Der Horst, Jan H.J. Hoeijmakers, Jan Vijg, Harry Van Steeg

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging, and cancer. One of the most versatile defense mechanisms against the accumulation of DNA damage is nucleotide excision repair, in which, among others, the Xeroderma pigmentosum group C (XPC) and group A (XPA) proteins are involved. To elucidate differences in the functions of these two proteins, comprehensive survival studies with Xpa-/-, Xpc-/- and wild-type control female mice in a pure C57BL/6J background were done. The median survival of Xpc-/- mice showed a significant decrease, whereas the median survival of Xpa-/- mice did not. Strikingly, Xpa-/- and Xpc-/- mice also showed a phenotypical difference in terms of tumor spectrum. Xpc-/- mice displayed a significant increase in lung tumors and a trend toward increased liver tumors compared with Xpa-deficient or wild-type mice. Xpa-/- mice showed a significant elevation in liver tumors. Additionally, Xpc-deficient mice exhibited a strong increase in mutant frequency in lung compared with Xpa-/- mice, whereas in both models mutant frequency is increased in liver. Our in vitro data displayed an elevated sensitivity to oxygen in Xpc -/- in mouse embryonic fibroblasts (MEF) when compared with Xpa -/- and wild-type fibroblasts. We believe that XPC plays a role in the removal of oxidative DNA damage and that, therefore, Xpc-/- mice display a significant increase in lung tumors and a significant elevation in mutant frequency in lung, and Xpc-deficient MEFs show greater sensitivity to oxygen when compared with Xpa-/- and wild-type mice.

Original languageEnglish (US)
Pages (from-to)1347-1353
Number of pages7
JournalCancer Research
Volume68
Issue number5
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Melis, J. P. M., Wijnhoven, S. W. P., Beems, R. B., Roodbergen, M., Van Den Berg, J., Moon, H., Friedberg, E., Van Der Horst, G. T. J., Hoeijmakers, J. H. J., Vijg, J., & Van Steeg, H. (2008). Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Cancer Research, 68(5), 1347-1353. https://doi.org/10.1158/0008-5472.CAN-07-6067