Human POLB Gene Is Mutated in High Percentage of Colorectal Tumors*
| Autor: | Ka-Wai Sun, Antonia A. Nemec, Veronika Northrup, Katherine A. Donigan, Xiangyu Cong, Drew L. Murphy, Joann B. Sweasy, Daniel Zelterman |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Genome instability
Models Molecular DNA repair DNA polymerase Cell Survival DNA polymerase beta DNA and Chromosomes medicine.disease_cause Biochemistry chemistry.chemical_compound Mice Mutation Rate medicine Animals Humans Molecular Biology Gene Cells Cultured DNA Polymerase beta Neoplasm Staging Mice Knockout Mutation Binding Sites biology Genetic Complementation Test Cell Biology Base excision repair Fibroblasts Embryo Mammalian Methyl Methanesulfonate Molecular biology Protein Structure Tertiary Kinetics HEK293 Cells chemistry Amino Acid Substitution biology.protein Biocatalysis Carcinogenesis Colorectal Neoplasms Mutagens |
| Popis: | 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. Background: Previous small scale studies indicate that DNA polymerase β variants are present in 30% of human tumors. Results: 40% of samples in a large human colorectal tumor collection harbor coding region variants, many of which exhibit altered function. Conclusion: Aberrant activity or fidelity phenotypes exhibited by variants may contribute to tumorigenesis. Significance: Expression of variants in human tumors plays a role in driving carcinogenesis. |
| Databáze: | OpenAIRE |
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