DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

doi:10.1073/pnas.0306551101

DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen

Divisions of ^*Biochemistry and Molecular Biology and ^‡Immunology and Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202; and ^§Department of Dermatology, Jikei University School of Medicine, Tokyo 105-8461, Japan

Edited by Carlo M. Croce, Thomas Jefferson University, Philadelphia, PA, and approved December 22, 2003 (received for review October 9, 2003)

Abstract

Mutations in the human DDB2 gene give rise to xeroderma pigmentosum group E, a disease characterized by increased skin tumorigenesis in response to UV-irradiation. Cell strains derived from xeroderma pigmentosum group E individuals also have enhanced resistance to UV-irradiation due to decreased p53-mediated apoptosis. To further address the precise function(s) of DDB2 and the consequence of non-naturally occurring DDB2 mutations, we generated mice with a disruption of the gene. The mice exhibited significantly enhanced skin carcinogenesis in response to UV-irradiation, and cells from the DDB2^–/– mice were abnormally resistant to killing by the radiation and had diminished UV-induced, p53-mediated apoptosis. Notably, the cancer-prone phenotype and the resistance to cellular killing were not observed after exposure to the chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), to which mice carrying defective nucleotide excision repair genes respond with enhanced tumors and cell killing. Although cells from heterozygous DDB2^+/– mice appeared normal, these mice had enhanced skin carcinogenesis after UV-irradiation, so that XP-E heterozygotes might be at risk for carcinogenesis. In sum, these results demonstrate that DDB2 is well conserved between humans and mice and functions as a tumor suppressor, at least in part, by controlling p53-mediated apoptosis after UV-irradiation.

Footnotes

↵ † To whom correspondence may be addressed. E-mail: slinn{at}socrates.berkeley.edu or toshiki{at}uclink4.berkeley.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: DMBA, 7,12-dimethylbenz[a]anthracene; ES, embryonic stem; MEF, mouse embryonic fibroblast; NER, nucleotide excision repair; XP, xeroderma pigmentosum; XP-E, XP group E.