The S229L colon tumor-associated variant of DNA polymerase β induces cellular transformation as a result of decreased polymerization efficiency

Antonia A. Nemec, Drew L. Murphy, Katherine A. Donigan, Joann B. Sweasy

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

DNA polymerase β (Pol β) plays a key role in base excision repair (BER) by filling in small gaps that are generated after base adducts are excised from the DNA. Pol β is mutated in a large number of colorectal tumors, and these mutations may drive carcinogenesis. In the present study, we wished to determine whether the S229L somatic Pol β variant identified in a stage 3 colorectal tumor is a driver of carcinogenesis. We show that S229L does not possess any defects in binding to either DNA or nucleotides compared with theWTenzyme, but exhibits a significant loss of polymerization efficiency, largely due to an 8-fold decrease in the polymerization rate. S229L participates in BER, but due to its lower catalytic rate, does so more slowly than WT. Expression of S229L in mammalian cells induces the accumulation of BER intermediate substrates, chromosomal aberrations, and cellular transformation. Our results are consistent with the interpretation that S229L is a driver of carcinogenesis, likely as a consequence of its slow polymerization activity during BER in vivo.

Original languageEnglish (US)
Pages (from-to)13708-13716
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number20
DOIs
StatePublished - May 16 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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