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Conserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes

dc.contributor.authorTsutakawa, Susan E.
dc.contributor.authorShin, David S.
dc.contributor.authorMol, Clifford D.
dc.contributor.authorLzumi, Tadahide
dc.contributor.authorArwai, Andrew S.
dc.contributor.authorMantha, Anil K.
dc.contributor.authorSzczesny, Bartosz
dc.contributor.authorIvanov, Ivaylo N.
dc.contributor.authorHosfield, David J.
dc.contributor.authorMaiti, Buddhadev
dc.contributor.authorPique, Mike E.
dc.contributor.authorFrankel, Kenneth A.
dc.contributor.authorHitomi. Kenichi
dc.contributor.authorCunnigham, Richard, P.
dc.contributor.authorMitra, Sankar
dc.contributor.authorTainer, John A.
dc.date.accessioned2013-01-11T15:31:12Z
dc.date.available2013-01-11T15:31:12Z
dc.date.issued2013
dc.identifier.citationTsutakawa, S. E., Shin, D. S., Mol, C. D., Izumi, T., Arvai, A. S., Mantha, A. K., . . . Tainer, J. A. (2013). Conserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes. Journal of Biological Chemistry, 288(12), 8445-8455. doi: 10.1074/jbc.M112.422774en_US
dc.identifier.issn219258
dc.identifier.urihttp://kr.cup.edu.in/handle/32116/387
dc.description.abstractNon-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair,APsites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion, yet they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 ? resolution APE1-DNA product complex with Mg2+ and a 0.92 ? Nfo with three metal ions. Structural and biochemical comparisons of these two evolutionarily distinct enzymes characterize keyAPE1catalytic residues that are potentially functionally similar to Nfo active site components, as further tested and supported by computational analyses. We observe a magnesium-water cluster in the APE1 active site, with only Glu-96 forming the direct protein coordination to the Mg2+. Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collectively, the results illuminate the activities of residues, metal ions, and active site features for abasic site endonucleases.en_US
dc.language.isoenen_US
dc.subjectActive site structureen_US
dc.subjectBase excision repairsen_US
dc.subjectCatalytic reactionsen_US
dc.subjectComputational analysisen_US
dc.subjectDNA-repair enzymesen_US
dc.subjectFunctional equivalenceen_US
dc.subjectGeometric conservationsen_US
dc.subjectStructural chemistryen_US
dc.subjectCatalysisen_US
dc.subjectDNAen_US
dc.subjectEnzymesen_US
dc.subjectMetal ionsen_US
dc.subjectRepairen_US
dc.subjectDNA (apurinic or apyrimidinic site) lyaseen_US
dc.subjectDouble stranded DNAen_US
dc.subjectEndonucleaseen_US
dc.subjectEndonuclease APE1en_US
dc.subjectGlutamineen_US
dc.subjectLysineen_US
dc.subjectMagnesiumen_US
dc.subjectPolydeoxyribonucleotide synthaseen_US
dc.subjectTetrahydrofuranen_US
dc.subjectUnclassified drugen_US
dc.subjectCatalysisen_US
dc.subjectControlled studyen_US
dc.subjectCrysen_US
dc.titleConserved structural chemistry for incision activity in structurally non-homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymesen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.M112.422774
dc.identifier.urlhttp://www.jbc.org/content/288/12/8445
dc.title.journalJournal of Biological Chemistry


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