8uks | pdb_00008uks

RNA polymerase II elongation complex with Fapy-dG lesion soaking with CTP before chemistry

spinqualitylabelsall models 8uks, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8uks is a 10 chain structure with sequence from Saccharomyces cerevisiae S288C and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.4Å Ligands: CTP, MG, WVQ, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Oxidative DNA lesions cause significant detrimental effects on a living species. Two major DNA lesions resulting from dG oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo) and formamidopyrimidine (Fapy.dG), are produced from a common chemical intermediate. Fapy.dG is formed in comparable yields under oxygen-deficient conditions. Replicative bypass of Fapy.dG in human cells is more mutagenic than that of 8-OxodGuo. Despite the biological importance of transcriptional mutagenesis, there are no reports of the effects of Fapy.dG on RNA polymerase II (Pol II) activity. Here we perform comprehensive kinetic studies to investigate the impact of Fapy.dG on three key transcriptional fidelity checkpoint steps by Pol II: insertion, extension, and proofreading steps. The ratios of error-free versus error-prone incorporation opposite Fapy.dG are significantly reduced in comparison with undamaged dG. Similarly, Fapy.dG:A mispair is extended with comparable efficiency as that of the error-free, Fapy.dG:C base pair. The alpha- and beta-configurational isomers of Fapy.dG have distinct effects on Pol II insertion and extension. Pol II can preferentially cleave error-prone products by proofreading. To further understand the structural basis of transcription processing of Fapy.dG, five different structures were solved, including Fapy.dG template-loading state (apo), error-free cytidine triphosphate (CTP) binding state (prechemistry), error-prone ATP binding state (prechemistry), error-free Fapy.dG:C product state (postchemistry), and error-prone Fapy.dG:A product state (postchemistry), revealing distinctive nucleotide binding and product states. Taken together, our study provides a comprehensive mechanistic framework for better understanding how Fapy.dG lesions impact transcription and subsequent pathological consequences. Molecular Mechanism of RNA Polymerase II Transcriptional Mutagenesis by the Epimerizable DNA Lesion, Fapy.dG.,Gao S, Hou P, Oh J, Wang D, Greenberg MM J Am Chem Soc. 2024 Mar 6;146(9):6274-6282. doi: 10.1021/jacs.3c14476. Epub 2024 , Feb 23. PMID:38393762 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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