title: Systematic biochemical analysis of somatic missense mutations in DNA polymerase β found in prostate cancer reveal alteration of enzymatic function.
abstract: DNA polymerase β is essential for short-patch base excision repair. We have previously identified 20 somatic pol β mutations in prostate tumors, many of them missense. In the current article we describe the effect of all of these somatic missense pol β mutations (p.K27N, p.E123K, p.E232K, p.P242R, p.E216K, p.M236L, and the triple mutant p.P261L/T292A/I298T) on the biochemical properties of the polymerase in vitro, following bacterial expression and purification of the respective enzymatic variants. We report that all missense somatic pol β mutations significantly affect enzyme function. Two of the pol β variants reduce catalytic efficiency, while the remaining five missense mutations alter the fidelity of DNA synthesis. Thus, we conclude that a significant proportion (9 out of 26; 35%) of prostate cancer patients have functionally important somatic mutations of pol β. Many of these missense mutations are clonal in the tumors, and/or are associated with loss of heterozygosity and microsatellite instability. These results suggest that interfering with normal polymerase β function may be a frequent mechanism of prostate tumor progression. Furthermore, the availability of detailed structural information for pol β allows understanding of the potential mechanistic effects of these mutants on polymerase function.
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, Tulane University, New Orleans, Louisiana 70112, USA.
authors.forename: Chang Long
authors.initials: CL
authors.lastname: An
authors.forename: Desheng
authors.initials: D
authors.lastname: Chen
authors.forename: Nick M
authors.initials: NM
authors.lastname: Makridakis
mesh_terms: D019951:DNA Polymerase beta / Q000235:genetics*; D004261:DNA Replication; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D019951:DNA Polymerase beta