A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant.

ABSTRACT: K289M is a variant of DNA polymerase β (pol β) that has previously been identified in colorectal cancer. The expression of this variant leads to a 16-fold increase in mutation frequency at a specific site in vivo and a reduction in fidelity in vitro in a sequence context-specific manner. Previous work shows that this reduction in fidelity results from a decreased level of discrimination against incorrect nucleotide incorporation at the level of polymerization. To probe the transition state of the K289M mutator variant of pol β, single-turnover kinetic experiments were performed using β,γ-CXY dGTP analogues with a wide range of leaving group monoacid dissociation constants (pK_a4), including a corresponding set of novel β,γ-CXY dCTP analogues. Surprisingly, we found that the value

SUBMITTER: Alnajjar KS 

PROVIDER: S-EPMC5522186 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature