Translesion synthesis past acrolein-derived DNA adduct, gamma -hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta

Irina G Minko; M Todd Washington; Manorama Kanuri; Louise Prakash; Satya Prakash; R Stephen Lloyd

doi:10.1074/jbc.M207774200

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Translesion synthesis past acrolein-derived DNA adduct, gamma -hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta

Journal article

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Translesion synthesis past acrolein-derived DNA adduct, gamma -hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta

Irina G Minko, M Todd Washington, Manorama Kanuri, Louise Prakash, Satya Prakash and R Stephen Lloyd

The Journal of biological chemistry, Vol.278(2), pp.784-790

01/10/2003

DOI: 10.1074/jbc.M207774200

PMID: 12401796

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Abstract

gamma-Hydroxy-1,N(2)-propano-2'deoxyguanosine (gamma-HOPdG) is a major deoxyguanosine adduct derived from acrolein, a known mutagen. In vitro, this adduct has previously been shown to pose a severe block to translesion synthesis by a number of polymerases (pol). Here we show that both yeast and human pol eta can incorporate a C opposite gamma-HOPdG at approximately 190- and approximately 100-fold lower efficiency relative to the control deoxyguanosine and extend from a C paired with the adduct at approximately 8- and approximately 19-fold lower efficiency. Although DNA synthesis past gamma-HOPdG by yeast pol eta was relatively accurate, the human enzyme misincorporated nucleotides opposite the lesion with frequencies of approximately 10(-1) to 10(-2). Because gamma-HOPdG can adopt both ring closed and ring opened conformations, comparative replicative bypass studies were also performed with two model adducts, propanodeoxyguanosine and reduced gamma-HOPdG. For both yeast and human pol eta, the ring open reduced gamma-HOPdG adduct was less blocking than gamma-HOPdG, whereas the ring closed propanodeoxyguanosine adduct was a very strong block. Replication of DNAs containing gamma-HOPdG in wild type and xeroderma pigmentosum variant cells revealed a somewhat decreased mutation frequency in xeroderma pigmentosum variant cells. Collectively, the data suggest that pol eta might potentially contribute to both error-free and mutagenic bypass of gamma-HOPdG.

Humans

Acrolein - toxicity

DNA Adducts - chemistry

DNA Replication

DNA-Directed DNA Polymerase - physiology

Deoxyguanosine - metabolism

Saccharomyces cerevisiae Proteins - physiology

Acrolein - metabolism

DNA Adducts - metabolism

Details

Title: Subtitle: Translesion synthesis past acrolein-derived DNA adduct, gamma -hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta
Creators: Irina G Minko - Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555, USA
M Todd Washington
Manorama Kanuri
Louise Prakash
Satya Prakash
R Stephen Lloyd
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.278(2), pp.784-790
DOI: 10.1074/jbc.M207774200
PMID: 12401796
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: GM19261 / NIGMS NIH HHS ES00267 / NIEHS NIH HHS ES06676 / NIEHS NIH HHS
Language: English
Date published: 01/10/2003
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984025393902771

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