Human POLB Gene Is Mutated in High Percentage of Colorectal Tumors

Abstract

Background:Previous small scale studies indicate that DNA polymerase ␤ variants are present in 30% of human tumors. Results: 40% of samples in a large human colorectal tumor collection harbor coding region variants, many of which exhibit altered function. Conclusion: Aberrant activity or fidelity phenotypes exhibited by variants may contribute to tumorigenesis. Significance: Expression of variants in human tumors plays a role in driving carcinogenesis.

Colon Cancer-associated DNA Polymerase β Variant Induces Genomic Instability and Cellular Transformation

“…In an initial activity screen it was shown that G231D pol ␤ exhibits a slower rate of DNA synthesis compared with WT pol ␤ in the primer extension assay (24). Here, we show that G231D exhibits a slower catalytic rate compared with WT using the 45AG DNA substrate in pre-steady state burst assays (Table 1).…”

“…The G231D variant of pol ␤ was identified in a colon tumor diagnosed as a stage 3 adenocarcinoma as described in the accompanying article (24). This variant was predicted to be damaging (24) and shown to catalyze DNA synthesis with a rate that is much lower than that of WT pol ␤.…”

“…This variant was predicted to be damaging (24) and shown to catalyze DNA synthesis with a rate that is much lower than that of WT pol ␤. The Gly-231 residue is in close proximity to DNA, and its alteration could therefore influence catalysis.…”

The Structural Location of DNA Lesions in Nucleosome Core Particles Determines Accessibility by Base Excision Repair Enzymes

“…The pol ␤ extension activity in NCPs was normalized to the maximum extension activity by pol ␤ on the corresponding free DNA to account for sequence preferences. Normalized data from either assay were fitted to a single phase exponential curve using GraphPad Prism version 6 and the equation Y ϭ Y max (1 Ϫ e Ϫkobst ), as performed previously by others (32,45). The initial rate of extension by pol ␤ was calculated by multiplying k obs and the corresponding Y max values.…”

The E295K Cancer Variant of Human Polymerase β Favors the Mismatch Conformational Pathway during Nucleotide Selection

“…The E295K variant of pol ␤ was first identified in a gastric carcinoma and subsequently found by us in a colon carcinoma (21,22). Expression of the E295K variant in mouse mammary epithelial cells induces sister chromatid exchanges and cellular transformation (23).…”