ArticleProceedings of the National Academy of Sciences of the United States of America2014
Variants of mouse DNA polymerase κ reveal a mechanism of efficient and accurate translesion synthesis past a benzo[a]pyrene dG adduct.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- Protein Assemblies in Translesion Synthesis.Genes · 2024Review
- Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ.Journal of chemical information and modeling · 2024Article
- Structural and Molecular Kinetic Features of Activities of DNA Polymerases.International journal of molecular sciences · 2022Review
- Identification and Characterization of Thermostable Y-Family DNA Polymerases η, ι, κ and Rev1 From a Lower Eukaryote,Frontiers in molecular biosciences · 2021Article
- Structure and function relationships in mammalian DNA polymerases.Cellular and molecular life sciences : CMLS · 2020Review
- Mammalian DNA Polymerase Kappa Activity and Specificity.Molecules (Basel, Switzerland) · 2019Review
- 2.0 Å resolution crystal structure of human polκ reveals a new catalytic function of N-clasp in DNA replication.Scientific reports · 2018Article
- Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism.Annual review of biochemistry · 2018Review
- Translesion Synthesis DNA Polymerase Kappa Is Indispensable for DNA Repair Synthesis in Cisplatin Exposed Dorsal Root Ganglion Neurons.Molecular neurobiology · 2018Article
- Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.Nature communications · 2017Article
- Translesion DNA polymerases in eukaryotes: what makes them tick?Critical reviews in biochemistry and molecular biology · 2017Review
- Translesion Synthesis of 2'-Deoxyguanosine Lesions by Eukaryotic DNA Polymerases.Chemical research in toxicology · 2017Article
- Review
- Translesion Synthesis of the N(2)-2'-Deoxyguanosine Adduct of the Dietary Mutagen IQ in Human Cells: Error-Free Replication by DNA Polymerase κ and Mutagenic Bypass by DNA Polymerases η, ζ, and Rev1.Chemical research in toxicology · 2016Article
- Structure and mechanism of error-free replication past the major benzo[a]pyrene adduct by human DNA polymerase κ.Nucleic acids research · 2016Article
- Comparative Error-Free and Error-Prone Translesion Synthesis of N(2)-2'-Deoxyguanosine Adducts Formed by Mitomycin C and Its Metabolite, 2,7-Diaminomitosene, in Human Cells.Chemical research in toxicology · 2016Article
- Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η.Nucleic acids research · 2016Article
- Effects of the N terminus of mouse DNA polymerase κ on the bypass of a guanine-benzo[a]pyrenyl adduct.Journal of biochemistry · 2016Article
- Regulation of Rad6/Rad18 Activity During DNA Damage Tolerance.Annual review of biophysics · 2015Review
- Structural and dynamic characterization of polymerase κ's minor groove lesion processing reveals how adduct topology impacts fidelity.Biochemistry · 2014Article
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8 authors at 5 institutions in 2 countries.
Funding
Abstract
DNA polymerase κ (Polκ) is the only known Y-family DNA polymerase that bypasses the 10S (+)-trans-anti-benzo[a]pyrene diol epoxide (BPDE)-N(2)-deoxyguanine adducts efficiently and accurately. The unique features of Polκ, a large structure gap between the catalytic core and little finger domain and a 90-residue addition at the N terminus known as the N-clasp, may give rise to its special translesion capability. We designed and constructed two mouse Polκ variants, which have reduced gap size on both sides [Polκ Gap Mutant (PGM) 1] or one side flanking the template base (PGM2). These Polκ variants are nearly as efficient as WT in normal DNA synthesis, albeit with reduced accuracy. However, PGM1 is strongly blocked by the 10S (+)-trans-anti-BPDE-N(2)-dG lesion. Steady-state kinetic measurements reveal a significant reduction in efficiency of dCTP incorporation opposite the lesion by PGM1 and a moderate reduction by PGM2. Consistently, Polκ-deficient cells stably complemented with PGM1 GFP-Polκ remained hypersensitive to BPDE treatment, and complementation with WT or PGM2 GFP-Polκ restored BPDE resistance. Furthermore, deletion of the first 51 residues of the N-clasp in mouse Polκ (mPolκ(52-516)) leads to reduced polymerization activity, and the mutant PGM2(52-516) but not PGM1(52-516) can partially compensate the N-terminal deletion and restore the catalytic activity on normal DNA. However, neither WT nor PGM2 mPolκ(52-516) retains BPDE bypass activity. We conclude that the structural gap physically accommodates the bulky aromatic adduct and the N-clasp is essential for the structural integrity and flexibility of Polκ during translesion synthesis.
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