Human POLB gene is mutated in high percentage of colorectal tumors

Katherine A. Donigan, Ka Wai Sun, Antonia A. Nemec, Drew L. Murphy, Xiangyu Cong, Veronika Northrup, Daniel Zelterman, Joann B. Sweasy

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Previous small scale sequencing studies have indicated that DNA polymerase β (pol β) variants are present on average in 30% of human tumors of varying tissue origin. Many of these variants have been shown to have aberrant enzyme function in vitro and to induce cellular transformation and/or genomic instability in vivo, suggesting that their presence is associated with tumorigenesis or its progression. In this study, the human POLB gene was sequenced in a collection of 134 human colorectal tumors and was found to contain coding region mutations in 40% of the samples. The variants map to many different sites of the pol β protein and are not clustered. Many variants are nonsynonymous amino acid substitutions predicted to affect enzyme function. A subset of these variants was found to have reduced enzyme activity in vitro and failed to fully rescue pol β-deficient cells from methylmethane sulfonate-induced cytotoxicity. Tumors harboring variants with reduced enzyme activity may have compromised base excision repair function, as evidenced by our methylmethane sulfonate sensitivity studies. Such compromised base excision repair may drive tumorigenesis by leading to an increase in mutagenesis or genomic instability.

Original languageEnglish (US)
Pages (from-to)23830-23839
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number28
DOIs
StatePublished - Jul 6 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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