5w2a | pdb_00005w2a
Structure of human DNA polymerase kappa in complex with Lucidin-derived DNA adduct and incoming dCMPNPP
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] Publication Abstract from PubMedDNA damage impinges on genetic information flow and has significant implications in human disease and aging. Lucidin-3-O-primeveroside (LuP) is an anthraquinone derivative present in madder root, which has been used as a coloring agent and food additive. LuP can be metabolically converted to genotoxic compound lucidin, which subsequently forms lucidin-specific N2-2'-deoxyguanosine (N2-dG) and N6-2'-deoxyadenosine (N6-dA) DNA adducts. Lucidin is mutagenic and carcinogenic in rodents, but has low carcinogenic risks in humans. To understand the molecular mechanism of low carcinogenicity of lucidin in humans, we performed DNA replication assays using site-specifically modified oligonucleotides containing a structural analogue (LdG) of lucidin-N2-dG DNA adduct and determined the crystal structures of DNA polymerase (pol) kappa in complex with LdG-bearing DNA and an incoming nucleotide. We examined four human pols (pol eta, pol iota, pol kappa, and Rev1) in their efficiency and accuracy during DNA replication with LdG; these pols are key players in DNA damage response. Our results demonstrate that pol kappa efficiently and accurately replicates past the LdG adduct, whereas DNA replication by pol eta, pol iota, and Rev1 is compromised to different extents. Two ternary crystal structures of pol kappa illustrate that the LdG adduct is accommodated by pol kappa at the enzyme active site during insertion and postlesion-extension steps. The unique open active site of pol kappa allows the adducted DNA to adapt a standard B-form for accurate DNA replication. Collectively, these biochemical and structural data provide mechanistic insights into the low carcinogenic risk of lucidin in humans. Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase kappa.,Yockey O, Jha V, Ghodke PP, Xu T, Xu W, Ling H, Pradeepkumar PI, Zhao L Chem Res Toxicol. 2017 Oct 3. doi: 10.1021/acs.chemrestox.7b00227. PMID:28972744[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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