3in5
From Proteopedia
Structure of human DNA polymerase kappa inserting dATP opposite an 8-oxoG DNA lesion
Structural highlights
Function[POLK_HUMAN] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.[1] [2] [3] [4] [5] [6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA and 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the major lesions formed. It is amongst the most mutagenic lesions in cells because of its dual coding potential, wherein 8-oxoG(syn) can pair with an A in addition to normal base pairing of 8-oxoG(anti) with a C. Human DNA polymerase kappa (Polkappa) is a member of the newly discovered Y-family of DNA polymerases that possess the ability to replicate through DNA lesions. To understand the basis of Polkappa's preference for insertion of an A opposite 8-oxoG lesion, we have solved the structure of Polkappa in ternary complex with a template-primer presenting 8-oxoG in the active site and with dATP as the incoming nucleotide. METHODOLOGY AND PRINCIPAL FINDINGS: We show that the Polkappa active site is well-adapted to accommodate 8-oxoG in the syn conformation. That is, the polymerase and the bound template-primer are almost identical in their conformations to that in the ternary complex with undamaged DNA. There is no steric hindrance to accommodating 8-oxoG in the syn conformation for Hoogsteen base-paring with incoming dATP. CONCLUSIONS AND SIGNIFICANCE: The structure we present here is the first for a eukaryotic translesion synthesis (TLS) DNA polymerase with an 8-oxoG:A base pair in the active site. The structure shows why Polkappa is more efficient at inserting an A opposite the 8-oxoG lesion than a C. The structure also provides a basis for why Polkappa is more efficient at inserting an A opposite the lesion than other Y-family DNA polymerases. Structure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion.,Vasquez-Del Carpio R, Silverstein TD, Lone S, Swan MK, Choudhury JR, Johnson RE, Prakash S, Prakash L, Aggarwal AK PLoS One. 2009 Jun 2;4(6):e5766. PMID:19492058[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: DNA-directed DNA polymerase | Human | Large Structures | Aggarwal, A K | Carpio, R Vasquez-Del | Silverstein, T D | Alternative splicing | Dna damage | Dna repair | Dna replication | Dna synthesis | Dna-binding | Dna-directed dna polymerase | Magnesium | Metal-binding | Mutator protein | Nucleotidyltransferase | Nucleus | Phosphoprotein | Polymorphism | Schiff base | Transferase | Transferase-dna complex | Zinc | Zinc-finger
