A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment.

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Research Abstract Details 

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A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Abstract Text:

Jacob Bauer,Guangxin Xing,Haruhiko Yagi,Jane M Sayer,Donald M Jerina,Hong Ling,

Erroneous replication of lesions in DNA by DNA polymerases leads to elevated mutagenesis. To understand the molecular basis of DNA damage-induced mutagenesis, we have determined the x-ray structures of the Y-family polymerase, Dpo4, in complex with a DNA substrate containing a bulky DNA lesion and incoming nucleotides. The DNA lesion is derived from an environmentally widespread carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BP). The potent carcinogen BP is metabolized to diol epoxides that form covalent adducts with cellular DNA. In the present study, the major BP diol epoxide adduct in DNA, BP-N(2)-deoxyguanosine (BP-dG), was placed at a template-primer junction. Three ternary complexes reveal replication blockage, extension past a mismatched lesion, and a -1 frameshift mutation. In the productive structures, the bulky adduct is flipped/looped out of the DNA helix into a structural gap between the little finger and core domains. Sequestering of the hydrophobic BP adduct in this new substrate-binding site permits the DNA to exhibit normal geometry for primer extension. Extrusion of the lesion by template misalignment allows the base 5' to the adduct to serve as the template, resulting in a -1 frameshift. Subsequent strand realignment produces a mismatched base opposite the lesion. These structural observations, in combination with replication and mutagenesis data, suggest a model in which the additional substrate-binding site stabilizes the extrahelical nucleotide for lesion bypass and generation of base substitutions and -1 frameshift mutations.

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Publishing Authors By Initials

J Bauer,G Xing,H Yagi,JM Sayer,DM Jerina,H Ling,

For similar genetic structures: templates, genetic research abstracts see: genetic structures: templates, genetic research

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A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 14905-10

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 11

MONTH: 09

YEAR: 2007

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Keywords Mesh Terms:

KEYWORDS: Templates, Genetic

MESH TERMS: metabolism

Chemical & Substance for Abstract: A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment. Information

Substance Name: DNA Polymerase beta

Registry Number: EC 2.7.7.-

Grant and Affiliation Information for A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment.

AFFILIATION: Department of Biochemistry, University of Western Ontario, London, ON, Canada N6A 5C1.

Country: United States

AGENCY: United States NIGMS

GRANT: GM0225180

ACRONYM: GM

MEDLINETA: Proc Natl Acad Sci U S A

REFSOURCE: Proc Natl Acad Sci U S A. 2007 Oct 23;10

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