Prostate-Cancer-Associated I260M Variant of DNA Polymerase β Is a Sequence-Specific Mutator

Studies show that 30% of 189 tumors sequenced to date express variants of the polymerase β (pol β) protein that are not present in normal tissue. This raises the possibility that variants of pol β might be linked to the etiology of cancer. Here, we characterize the I260M prostate-cancer-associated v...

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Bibliographic Details
Published in:Biochemistry (Easton) 2005-12, Vol.44 (48), p.15664-15673
Main Authors: Dalal, Shibani, Hile, Suzanne, Eckert, Kristin A, Sun, Ka-wai, Starcevic, Daniela, Sweasy, Joann B
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Cell Transformation, Neoplastic - genetics
Circular Dichroism
DNA Polymerase beta - genetics
DNA Polymerase beta - metabolism
DNA Repair - physiology
DNA, Circular
Humans
Male
Mice
Molecular Sequence Data
Mutation - genetics
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - genetics
Protein Folding
Templates, Genetic
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Summary:Studies show that 30% of 189 tumors sequenced to date express variants of the polymerase β (pol β) protein that are not present in normal tissue. This raises the possibility that variants of pol β might be linked to the etiology of cancer. Here, we characterize the I260M prostate-cancer-associated variant of pol β. 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.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi051179z