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Systematic biochemical analysis of somatic missense mutations in DNA polymerase β found in prostate cancer reveal alteration of enzymatic function
Author(s) -
An Chang Long,
Chen Desheng,
Makridakis Nick M.
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21465
Subject(s) - missense mutation , biology , dna polymerase beta , polymerase , dna polymerase , genetics , somatic cell , dna repair , microsatellite instability , mutant , base excision repair , germline mutation , mutation , loss of heterozygosity , cancer research , microbiology and biotechnology , dna , gene , microsatellite , allele
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. Hum Mutat 32:1–9, 2011. © 2011 Wiley‐Liss, Inc.