Expression of DNA Polymerase β Cancer-Associated Variants in Mouse Cells Results in Cellular Transformation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 40; pp. 14350 - 14355
• Main Authors: Sweasy, Joann B., Lang, Tieming, Starcevic, Daniela, Sun, Ka-Wai, Lai, Char-Chang, DiMaio, Daniel, Dalal, Shibani, Hanawalt, Philip C.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 04-10-2005; National Acad Sciences
• Subjects: Biochemistry; Biological Sciences; Cancer; Carcinoma; Cell growth; Cell lines; Cells; Deoxyribonucleic acid; DNA; Enzymes; Flasks; Gene expression; Genetic mutation; Mutation; Phenotypes; Rodents; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505166102

Thirty percent of the 189 tumors studied to date express DNA polymerase β variants. One of these variants was identified in a prostate carcinoma and is altered from isoleucine to methionine at position 260, within the hydrophobic hinge region of the protein. Another variant was identified in a colon carcinoma and is altered at position 289 from lysine to methionine, within helix N of the protein. We have shown that the types of mutations induced by these cancer-associated variants are different from those induced by the wild-type enzyme. In this study, we show that expression of the 1260M and K289M cancer-associated variants in mouse C127 cells results in a transformed phenotype in the great majority of cell clones tested, as assessed by focus formation and anchorage-independent growth. Strikingly, cellular transformation occurs after a variable number of passages in culture but, once established, does not require continuous expression of the polymerase β variant proteins, implying that it has a mutational basis. Because DNA polymerase β functions in base excision repair, our results suggest that mutations that arise during this process can lead to the onset or progression of cancer.