Expression of DNA polymerase β cancer-associated variants in mouse cells results in cellular transformation
- Joann B. Sweasy*,†,‡,
- Tieming Lang*,†,
- Daniela Starcevic*,†,
- Ka-Wai Sun*,†,
- Char-Chang Lai†,
- Daniel DiMaio*,†, and
- Shibani Dalal*,†
- Departments of *Therapeutic Radiology and †Genetics, Yale University School of Medicine, New Haven, CT 06520
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Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved August 22, 2005 (received for review June 20, 2005)
Abstract
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 I260M 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.
Footnotes
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↵ ‡ To whom correspondence should be addressed at: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208040, New Haven, CT 06520. E-mail: joann.sweasy{at}yale.edu.
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Author contributions: J.B.S. and D.D. designed research; J.B.S., T.L., K.-W.S., and S.D. performed research; T.L., D.S., and C.-C.L. contributed new reagents/analytic tools; J.B.S., D.S., D.D., and S.D. analyzed data; and J.B.S. and D.D. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: BER, base excision repair; HA, hemagglutin in; pol β, polymerase β; Tet, tetracycline.
- Copyright © 2005, The National Academy of Sciences
