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 journalArticle

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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 - Jan 1 2018

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Acrolein
DNA Adducts
Nucleotides
Environmental Pollutants
Polyamines
Guanine
DNA-Directed DNA Polymerase
Aldehydes
Lipid Peroxidation
Molecular Biology
DNA
Cells
Lipids
Oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Genetic control of predominantly error-free replication through an acrolein-derived minor-groove DNA adduct. / Yoon, Jung Hoon; Hodge, Richard P.; Hackfeld, Linda C.; Park, Jeseong; Choudhury, Jayati Roy; Prakash, Satya; Prakash, Louise.

In: Journal of Biological Chemistry, Vol. 293, No. 8, 01.01.2018, p. 2949-2958.

Research output: Contribution to journalArticle

Yoon, Jung Hoon ; Hodge, Richard P. ; Hackfeld, Linda C. ; Park, Jeseong ; Choudhury, Jayati Roy ; Prakash, Satya ; Prakash, Louise. / Genetic control of predominantly error-free replication through an acrolein-derived minor-groove DNA adduct. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 8. pp. 2949-2958.
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AB - 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.

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