Prostate-cancer-associated I260M variant of DNA polymerase beta is a sequence-specific mutator
| Autor: | Joann B. Sweasy, Suzanne Hile, Ka Wai Sun, Daniela Starcevic, Shibani Dalal, Kristin A. Eckert |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Protein Folding DNA Repair DNA polymerase DNA polymerase II Molecular Sequence Data Biochemistry DNA polymerase delta chemistry.chemical_compound Mice Animals Humans Amino Acid Sequence Polymerase DNA Polymerase beta Genetics biology DNA synthesis Base Sequence Circular Dichroism Prostatic Neoplasms Templates Genetic Molecular biology Phenotype Cell Transformation Neoplastic chemistry Mutation biology.protein DNA Circular DNA polymerase mu DNA |
| Zdroj: | Biochemistry. 44(48) |
| ISSN: | 0006-2960 |
| Popis: | Studies show that 30% of 189 tumors sequenced to date express variants of the polymerase beta (pol beta) protein that are not present in normal tissue. This raises the possibility that variants of pol beta might be linked to the etiology of cancer. Here, we characterize the I260M prostate-cancer-associated variant of pol beta. Ile260 is a key residue of the hydrophobic hinge that is important for the closing of the polymerase. In this study, we demonstrate that the I260M variant is a sequence context-dependent mutator polymerase. Specifically, I260M is a mutator for misalignment-mediated errors in dipyrimidine sequences. I260M is also a low-fidelity polymerase with regard to the induction of transversions within specific sequence contexts. Our results suggest that the hinge influences the geometry of the DNA within the polymerase active site that is important for accurate DNA synthesis. Importantly, characterization of the I260M variant shows that it has a functional phenotype that could be linked to the etiology or malignant progression of human cancer. |
| Databáze: | OpenAIRE |
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