This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, Q. Articles by Kucherlapati, R. Search for Related Content PubMed PubMed Citation Articles by Lin, Q. Articles by Kucherlapati, R.

Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase –deficient Mice

¹ Harvard Medical School/Partners Healthcare Center for Genetics and Genomics; ² Harvard Medical School, Boston, Massachusetts; and ³ National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina

Requests for reprints: Raju Kucherlapati, Harvard Medical School/Partners Healthcare Center for Genetics and Genomics, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-525-4445; Fax: 617-525-4440; E-mail: rkucherlapati{at}partners.org.

Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase (pol ) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol to efficiently bypass UV light–induced cyclobutane pyrimidine dimers, XPV cells lacking Pol have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light–induced killing and mutagenesis. To better understand these and other Pol functions, we generated Pol –deficient mice. Mice homozygous for a null mutation in pol are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol –deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol indicate that Pol –dependent bypass of cyclobutane pyrimidine dimers suppresses UV light–induced skin cancer in mice. Moreover, 37.5% of pol heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol may also have an increased risk of skin cancer. (Cancer Res 2006; 66(1): 87-94)

This article has been cited by other articles:

				L. Rey, J. M. Sidorova, N. Puget, F. Boudsocq, D. S. F. Biard, R. J. Monnat Jr., C. Cazaux, and J.-S. Hoffmann Human DNA Polymerase {eta} Is Required for Common Fragile Site Stability during Unperturbed DNA Replication Mol. Cell. Biol., June 15, 2009; 29(12): 3344 - 3354. [Abstract] [Full Text] [PDF]

				A. Faili, A. Stary, F. Delbos, S. Weller, S. Aoufouchi, A. Sarasin, J.-C. Weill, and C.-A. Reynaud A Backup Role of DNA Polymerase {kappa} in Ig Gene Hypermutation Only Takes Place in the Complete Absence of DNA Polymerase {eta} J. Immunol., May 15, 2009; 182(10): 6353 - 6359. [Abstract] [Full Text] [PDF]

				S. D. McCulloch, R. J. Kokoska, P. Garg, P. M. Burgers, and T. A. Kunkel The efficiency and fidelity of 8-oxo-guanine bypass by DNA polymerases {delta} and {eta} Nucleic Acids Res., May 1, 2009; 37(9): 2830 - 2840. [Abstract] [Full Text] [PDF]

				R. A. Busuttil, Q. Lin, P. J. Stambrook, R. Kucherlapati, and J. Vijg Mutation Frequencies and Spectra in DNA Polymerase {eta}-Deficient Mice Cancer Res., April 1, 2008; 68(7): 2081 - 2084. [Abstract] [Full Text] [PDF]

				C. A. Dumstorf, A. B. Clark, Q. Lin, G. E. Kissling, T. Yuan, R. Kucherlapati, W. G. McGregor, and T. A. Kunkel Participation of mouse DNA polymerase {iota} in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer PNAS, November 28, 2006; 103(48): 18083 - 18088. [Abstract] [Full Text] [PDF]

				T. Ohkumo, Y. Kondo, M. Yokoi, T. Tsukamoto, A. Yamada, T. Sugimoto, R. Kanao, Y. Higashi, H. Kondoh, M. Tatematsu, et al. UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase {eta} and Mesenchymal Tumors in Mice Deficient for DNA Polymerase {iota} Mol. Cell. Biol., October 15, 2006; 26(20): 7696 - 7706. [Abstract] [Full Text] [PDF]

				J. Hagendoorn, R. Tong, D. Fukumura, Q. Lin, J. Lobo, T. P. Padera, L. Xu, R. Kucherlapati, and R. K. Jain Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res., April 1, 2006; 66(7): 3360 - 3364. [Abstract] [Full Text] [PDF]