ArticleNucleic acids research2016
Insertion of oxidized nucleotide triggers rapid DNA polymerase opening.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Machines on Genes through the Computational Microscope.Journal of chemical theory and computation · 2023Review
- A Role for N6-Methyladenine in DNA Damage Repair.Trends in biochemical sciences · 2021Review
- Molecular Mechanisms of DNA Replication and Repair Machinery: Insights from Microscopic Simulations.Advanced theory and simulations · 2019Article
- Competitive Binding of MgBiophysical journal · 2018Article
- Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants.Chemical research in toxicology · 2017Article
- The mChemical science · 2017Article
- Divalent Ion-Mediated DNA-DNA Interactions: A Comparative Study of Triplex and Duplex.Biophysical journal · 2017Article
- Protocols for Molecular Dynamics Simulations of RNA Nanostructures.Methods in molecular biology (Clifton, N.J.) · 2017Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
A novel mechanism is unveiled to explain why a pro-mutagenic nucleotide lesion (oxidized guanine, 8-oxoG) causes the mammalian DNA repair polymerase-β (pol-β) to rapidly transition to an inactive open conformation. The mechanism involves unexpected features revealed recently in time-lapse crystallography. Specifically, a delicate water network associated with a lesion-stabilizing auxilliary product ion Mg(p) triggers a cascade of events that leads to poor active site geometry and the rupture of crucial molecular interactions between key residues in both the anti(8-oxoG:C) and syn(8-oxoG:A) systems. Once the base pairs in these lesioned systems are broken, dislocation of both Asp192 (a metal coordinating ligand) and the oxoG phosphate group (PO4) interfere with the hydrogen bonding between Asp192 and Arg258, whose rotation toward Asp192 is crucial to the closed-to-open enzyme transition. Energetically, the lesioned open states are similar in energy to those of the corresponding closed complexes after chemistry, in marked contrast to the unlesioned pol-β anti(G:C) system, whose open state is energetically higher than the closed state. The delicate surveillance system offers a fundamental protective mechanism in the cell that triggers DNA repair events which help deter insertion of oxidized lesions.
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Registered trials
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