TY - JOUR
T1 - Mutagenic bypass of the butadiene-derived 2′-deoxyuridine adducts by polymerases η and ζ
AU - Fernandes, Priscilla H.
AU - Lloyd, R. Stephen
N1 - Funding Information:
We acknowledge Dr. Richard Hodge and Ms. Linda Hackfield, Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas for the BD N3-dU adducted oligodeoxynucleotides and Dr. Irina Minko for guidance on replication analyses. This work was supported by the NIH grant P01-ES05355 and NIEHS Center grants P30-ES06676 and P30-ES00267.
PY - 2007/12/1
Y1 - 2007/12/1
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.
AB - 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.
KW - Butadiene
KW - Butadiene-derived 2′-deoxyuridine adducts
KW - DNA adducts
KW - Translesion polymerases
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U2 - 10.1016/j.mrfmmm.2007.05.003
DO - 10.1016/j.mrfmmm.2007.05.003
M3 - Article
C2 - 17586533
AN - SCOPUS:35548963757
SN - 0027-5107
VL - 625
SP - 40
EP - 49
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2
ER -