Prostate-cancer-associated I260M variant of DNA polymerase beta is a sequence-specific mutator.
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.
Dalal
Shibani
S
Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Hile
Suzanne
S
Eckert
Kristin A
KA
Sun
Ka-wai
KW
Starcevic
Daniela
D
Sweasy
Joann B
JB
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002942:Circular Dichroism; D019951:DNA Polymerase beta / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004270:DNA, Circular; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D017510:Protein Folding; D013698:Templates, Genetic
D004270:DNA, Circular; D019951:DNA Polymerase beta