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, Shibani Dalal

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14350-14355
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number40
DOIs
StatePublished - Oct 4 2005
Externally publishedYes

Keywords

  • Base excision repair
  • DNA repair
  • Mutagenesis

ASJC Scopus subject areas

  • General

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