title: Human POLB gene is mutated in high percentage of colorectal tumors.
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.
authors.affiliation: Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Donigan
authors.forename: Ka-wai
authors.initials: KW
authors.lastname: Sun
authors.forename: Antonia A
authors.initials: AA
authors.lastname: Nemec
authors.forename: Drew L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Cong
authors.forename: Veronika
authors.initials: V
authors.lastname: Northrup
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D055162:Biocatalysis; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019951:DNA Polymerase beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D059645:Mutation Rate; D009367:Neoplasm Staging; D017434:Protein Structure, Tertiary
chemical_list: D009153:Mutagens; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta