Probing the Effect of Bulky Lesion-Induced Replication Fork Conformational Heterogeneity Using 4-Aminobiphenyl-Modified DNA

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Apr 24

PMID 31009995

Citations 1

Authors

Ang Cai

Ke Bian

Fangyi Chen

Qi Tang

Rachel Carley

Deyu Li

Bongsup P Cho

Affiliations

Soon will be listed here.

Abstract

Bulky organic carcinogens are activated in vivo and subsequently react with nucleobases of cellular DNA to produce adducts. Some of these DNA adducts exist in multiple conformations that are slowly interconverted to one another. Different conformations have been implicated in different mutagenic and repair outcomes. However, studies on the conformation-specific inhibition of replication, which is more relevant to cell survival, are scarce, presumably due to the structural dynamics of DNA lesions at the replication fork. It is difficult to capture the exact nature of replication inhibition by existing end-point assays, which usually detect either the ensemble of consequences of all the conformers or the culmination of all cellular behaviors, such as mutagenicity or survival rate. We previously reported very unusual sequence-dependent conformational heterogeneities involving FABP-modified DNA under different sequence contexts (TG*GT [67%B:33%S] and TGG*T [100%B], G*, -(2'-deoxyguanosin-8-yl)-4'-fluoro-4-aminobiphenyl) (Cai et al. , 46, 6356-6370 (2018)). In the present study, we attempted to correlate the in vitro inhibition of polymerase activity to different conformations from a single FABP-modified DNA lesion. We utilized a combination of surface plasmon resonance (SPR) and HPLC-based steady-state kinetics to reveal the differences in terms of binding affinity and inhibition with polymerase between these two conformers (67%B:33%S and 100%B).

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