Replication and Repair of a Reduced 2΄-deoxyguanosine-abasic Site Interstrand Cross-link in Human Cells

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Apr 22

PMID 28431012

Citations 14

Authors

Nathan E Price

Lin Li

Kent S Gates

Yinsheng Wang

Affiliations

Soon will be listed here.

Abstract

Apurinic/apyrimidinic (AP) sites, or abasic sites, which are a common type of endogenous DNA damage, can forge interstrand DNA-DNA cross-links via reaction with the exocyclic amino group on a nearby 2΄-deoxyguanosine or 2΄-deoxyadenosine in the opposite strand. Here, we utilized a shuttle vector method to examine the efficiency and fidelity with which a reduced dG-AP cross-link-containing plasmid was replicated in cultured human cells. Our results showed that the cross-link constituted strong impediments to DNA replication in HEK293T cells, with the bypass efficiencies for the dG- and AP-containing strands being 40% and 20%, respectively. While depletion of polymerase (Pol) η did not perturb the bypass efficiency of the lesion, the bypass efficiency was markedly reduced (to 1-10%) in the isogenic cells deficient in Pol κ, Pol ι or Pol ζ, suggesting the mutual involvement of multiple translesion synthesis polymerases in bypassing the lesion. Additionally, replication of the cross-linked AP residue in HEK293T cells was moderately error-prone, inducing a total of ∼26% single-nucleobase substitutions at the lesion site, whereas replication past the cross-linked dG component occurred at a mutation frequency of ∼8%. Together, our results provided important insights into the effects of an AP-derived interstrand cross-link on the efficiency and accuracy of DNA replication in human cells.

Citing Articles

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Structure of a Stable Interstrand DNA Cross-Link Involving a β--Glycosyl Linkage Between an -dA Amino Group and an Abasic Site.

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