Genetic control of predominantly error-free replication through an acrolein-derived minor-groove DNA adduct

Jung Hoon Yoon, Richard P. Hodge, Linda C. Hackfeld, Jeseong Park, Jayati Roy Choudhury, Satya Prakash, Louise Prakash

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Acrolein, anα,β-unsaturated aldehyde, is generated in vivo as the end product of lipid peroxidation and from metabolic oxidation of polyamines, and it is a ubiquitous environmental pollutant. The reaction of acrolein with the N2 of guanine in DNA leads to the formation of γ-hydroxy-1-N2-propano-2′ deoxyguanosine (γ-HOPdG), which can exist inDNAin a ring-closed or a ring-opened form. Here, we identified the translesion synthesis (TLS) DNA polymerases (Pols) that conduct replication through the permanently ring-opened reduced form of γ-HOPdG ((r) γ-HOPdG) and show that replication through this adduct is mediated via Rev1/Polη-, Poli/Polκ-, and Polθ- dependent pathways, respectively. Based on biochemical and structural studies, we propose a role for Rev1 and Poli in inserting a nucleotide (nt) opposite the adduct and for Polsη and κ in extending synthesis from the inserted nt in the respective TLS pathway. Based on genetic analyses and biochemical studies with Polθ, we infer a role for Polθ at both the nt insertion and extension steps of TLS. Whereas purified Rev1 and Polθ primarily incorporate a C opposite (r)γ-HOPdG, Poli incorporates a C or a T opposite the adduct; nevertheless, TLS mediated by the Poli-dependent pathway as well as by other pathways occurs in a predominantly error-free manner in human cells. We discuss the implications of these observations for the mechanisms that could affect the efficiency and fidelity of TLS Pols.

Original languageEnglish (US)
Pages (from-to)2949-2958
Number of pages10
JournalJournal of Biological Chemistry
Volume293
Issue number8
DOIs
StatePublished - Feb 23 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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