title: The human gastric cancer-associated DNA polymerase β variant D160N is a mutator that induces cellular transformation.
abstract: Approximately 30% of human tumors sequenced to date harbor mutations in the POLB gene that are not present in matched normal tissue. Many mutations give rise to enzymes that contain non-synonymous single amino acid substitutions, several of which have been found to have aberrant activity or fidelity and transform cells when expressed. The DNA Polymerase β (Pol β) variant Asp160Asn (D160N) was first identified in a gastric tumor. Expression of D160N in cells induces cellular transformation as measured by hyperproliferation, focus formation, anchorage-independent growth and invasion. Here, we show that D160N is an active mutator polymerase that induces complex mutations. Our data support the interpretation that complex mutagenesis is the underlying mechanism of the observed cellular phenotypes, all of which are linked to tumorigenesis or tumor progression.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, United States.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Donigan
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Hile
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Eckert
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D019951:DNA Polymerase beta / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins; D004247:DNA; D019951:DNA Polymerase beta; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus