ArticleProceedings of the National Academy of Sciences of the United States of America2007
A structural gap in Dpo4 supports mutagenic bypass of a major benzo[a]pyrene dG adduct in DNA through template misalignment.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers.
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52 citing papers in PubMed, 81 citations in OpenAlex.
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- A History of Cancer Research: Carcinogens and Mutagens.Cold Spring Harbor perspectives in medicine · 2021Review
- Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase.eLife · 2020Article
- Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism.Annual review of biochemistry · 2018Review
- Bulky Lesion Bypass Requires Dpo4 Binding in Distinct Conformations.Scientific reports · 2017Article
- Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ.Chemical research in toxicology · 2017Article
- Mechanism of error-free replication across benzo[a]pyrene stereoisomers by Rev1 DNA polymerase.Nature communications · 2017Article
- Pre-steady-state kinetic investigation of bypass of a bulky guanine lesion by human Y-family DNA polymerases.DNA repair · 2016Article
- Structure and mechanism of error-free replication past the major benzo[a]pyrene adduct by human DNA polymerase κ.Nucleic acids research · 2016Article
- Mechanism of aromatic amine carcinogen bypass by the Y-family polymerase, Dpo4.Nucleic acids research · 2015Article
- Mechanistic Basis for the Bypass of a Bulky DNA Adduct Catalyzed by a Y-Family DNA Polymerase.Journal of the American Chemical Society · 2015Article
- Mechanistic investigation of the bypass of a bulky aromatic DNA adduct catalyzed by a Y-family DNA polymerase.DNA repair · 2014Article
- Dynamic conformational change regulates the protein-DNA recognition: an investigation on binding of a Y-family polymerase to its target DNA.PLoS computational biology · 2014Article
- Biochemical characterization of eight genetic variants of human DNA polymerase κ involved in error-free bypass across bulky N(2)-guanyl DNA adducts.Chemical research in toxicology · 2014Article
- An overview of Y-Family DNA polymerases and a case study of human DNA polymerase η.Biochemistry · 2014Review
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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