Mutagenic bypass of the butadiene-derived 2′-deoxyuridine adducts by polymerases η and ζ

Priscilla H. Fernandes, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Butadiene is a ubiquitous environmental chemical carcinogen that when activated to its monoepoxide intermediate can react with the N3 position of cytosine, resulting in two stereoisomeric adducted bases that rapidly deaminate to N3 2′-deoxyuridine lesions. We have previously shown that replication of DNAs containing these adducts through mammalian cells resulted in ∼97% mutagenicity, predominantly C to T transitions. Since replicative DNA polymerases were blocked by these lesions in vitro, translesional polymerases were assessed for their ability to bypass these adducts. While polymerases ι, κ and ζ were significantly blocked one nucleotide prior to the lesion, pol η incorporated nucleotides opposite the adducts with a preference for insertion of a G or A. Following polymerase dissociation and reassociation, pol η was also able to extend primers with mispaired termini opposite the lesions, with extensions from the A and T mismatched primer termini being the most efficient. Pol ζ was also able to extend primers containing all mismatched nucleotides opposite the lesions, with the most efficient extension occurring off of the A mismatched primer.

Original languageEnglish (US)
Pages (from-to)40-49
Number of pages10
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume625
Issue number1-2
DOIs
StatePublished - Dec 1 2007

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Deoxyuridine
Nucleotides
Environmental Carcinogens
DNA Adducts
Cytosine
DNA-Directed DNA Polymerase
1,3-butadiene

Keywords

  • Butadiene
  • Butadiene-derived 2′-deoxyuridine adducts
  • DNA adducts
  • Translesion polymerases

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Mutagenic bypass of the butadiene-derived 2′-deoxyuridine adducts by polymerases η and ζ. / Fernandes, Priscilla H.; Lloyd, Robert (Stephen).

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 625, No. 1-2, 01.12.2007, p. 40-49.

Research output: Contribution to journalArticle

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N2 - Butadiene is a ubiquitous environmental chemical carcinogen that when activated to its monoepoxide intermediate can react with the N3 position of cytosine, resulting in two stereoisomeric adducted bases that rapidly deaminate to N3 2′-deoxyuridine lesions. We have previously shown that replication of DNAs containing these adducts through mammalian cells resulted in ∼97% mutagenicity, predominantly C to T transitions. Since replicative DNA polymerases were blocked by these lesions in vitro, translesional polymerases were assessed for their ability to bypass these adducts. While polymerases ι, κ and ζ were significantly blocked one nucleotide prior to the lesion, pol η incorporated nucleotides opposite the adducts with a preference for insertion of a G or A. Following polymerase dissociation and reassociation, pol η was also able to extend primers with mispaired termini opposite the lesions, with extensions from the A and T mismatched primer termini being the most efficient. Pol ζ was also able to extend primers containing all mismatched nucleotides opposite the lesions, with the most efficient extension occurring off of the A mismatched primer.

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