title: The S229L colon tumor-associated variant of DNA polymerase β induces cellular transformation as a result of decreased polymerization efficiency.
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 the WT enzyme, 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.
authors.affiliation: From the Departments of Therapeutic Radiology and Genetics, Yale University, New Haven, Connecticut 06520.
authors.forename: Antonia A
authors.initials: AA
authors.lastname: Nemec
authors.affiliation: From the Departments of Therapeutic Radiology and Genetics, Yale University, New Haven, Connecticut 06520.
authors.forename: Drew L
authors.initials: DL
authors.lastname: Murphy
authors.affiliation: From the Departments of Therapeutic Radiology and Genetics, Yale University, New Haven, Connecticut 06520.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Donigan
authors.affiliation: From the Departments of Therapeutic Radiology and Genetics, Yale University, New Haven, Connecticut 06520 joann.sweasy@yale.edu.
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019951:DNA Polymerase beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D015971:Gene Expression Regulation, Enzymologic; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D007700:Kinetics; D051379:Mice; D009154:Mutation; D009367:Neoplasm Staging; D009711:Nucleotides / Q000378:metabolism; D055503:Protein Multimerization / Q000235:genetics*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D009711:Nucleotides; D004247:DNA; D019951:DNA Polymerase beta
keywords: Base Excision Repair; Cancer; Genetics; Genomic Instability; Mutagenesis