Sequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1

Handle URI:
http://hdl.handle.net/10754/334510
Title:
Sequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1
Authors:
Sobhy, M.; Joudeh, L.; Huang, X.; Takahashi, Masateru; Hamdan, S.
Abstract:
Human flap endonuclease 1 (FEN1), one of the structure-specific 5' nucleases, is integral in replication, repair, and recombination of cellular DNA. The 5' nucleases share significant unifying features yet cleave diverse substrates at similar positions relative to 5' end junctions. Using single-molecule Förster resonance energy transfer, we find a multistep mechanism that verifies all substrate features before inducing the intermediary-DNA bending step that is believed to unify 5' nuclease mechanisms. This is achieved by coordinating threading of the 5' flap of a nick junction into the conserved capped-helical gateway, overseeing the active site, and bending by binding at the base of the junction. We propose that this sequential and multistep substrate recognition process allows different 5' nucleases to recognize different substrates and restrict the induction of DNA bending to the last common step. Such mechanisms would also ensure the protection ofDNA junctions from nonspecific bending and cleavage. 2013 The Authors.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Sobhy MA, Joudeh LI, Huang X, Takahashi M, Hamdan SM (2013) Sequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1. Cell Reports 3: 1785-1794. doi:10.1016/j.celrep.2013.05.001.
Publisher:
Elsevier BV
Journal:
Cell Reports
Issue Date:
6-Jun-2013
DOI:
10.1016/j.celrep.2013.05.001
Type:
Article
ISSN:
22111247
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorSobhy, M.en
dc.contributor.authorJoudeh, L.en
dc.contributor.authorHuang, X.en
dc.contributor.authorTakahashi, Masateruen
dc.contributor.authorHamdan, S.en
dc.date.accessioned2014-11-11T14:27:45Z-
dc.date.available2014-11-11T14:27:45Z-
dc.date.issued2013-06-06en
dc.identifier.citationSobhy MA, Joudeh LI, Huang X, Takahashi M, Hamdan SM (2013) Sequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1. Cell Reports 3: 1785-1794. doi:10.1016/j.celrep.2013.05.001.en
dc.identifier.issn22111247en
dc.identifier.doi10.1016/j.celrep.2013.05.001en
dc.identifier.urihttp://hdl.handle.net/10754/334510en
dc.description.abstractHuman flap endonuclease 1 (FEN1), one of the structure-specific 5' nucleases, is integral in replication, repair, and recombination of cellular DNA. The 5' nucleases share significant unifying features yet cleave diverse substrates at similar positions relative to 5' end junctions. Using single-molecule Förster resonance energy transfer, we find a multistep mechanism that verifies all substrate features before inducing the intermediary-DNA bending step that is believed to unify 5' nuclease mechanisms. This is achieved by coordinating threading of the 5' flap of a nick junction into the conserved capped-helical gateway, overseeing the active site, and bending by binding at the base of the junction. We propose that this sequential and multistep substrate recognition process allows different 5' nucleases to recognize different substrates and restrict the induction of DNA bending to the last common step. Such mechanisms would also ensure the protection ofDNA junctions from nonspecific bending and cleavage. 2013 The Authors.en
dc.language.isoenen
dc.publisherElsevier BVen
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectflap endonucleaseen
dc.subjectFlap endonuclease 1en
dc.subjectnucleotideen
dc.subjectunclassified drugen
dc.subject5' untranslated regionen
dc.subjectcontrolled studyen
dc.subjectDNA helixen
dc.subjectDNA modificationen
dc.subjectenzyme active siteen
dc.subjectenzyme assayen
dc.subjectenzyme bindingen
dc.subjectenzyme specificityen
dc.subjectenzyme substrateen
dc.subjectfluorescence resonance energy transferen
dc.subjectmolecular recognitionen
dc.subjectsequence analysisen
dc.subjectDNAen
dc.subjectDNA Replicationen
dc.subjectFlap Endonucleasesen
dc.subjectFluorescence Resonance Energy Transferen
dc.subjectKineticsen
dc.subjectModels, Molecularen
dc.subjectNucleic Acid Conformationen
dc.subjectSubstrate Specificityen
dc.titleSequential and Multistep Substrate Interrogation Provides the Scaffold for Specificity in Human Flap Endonuclease 1en
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalCell Reportsen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorSobhy, Mohamed Abdelmabouden
kaust.authorHuang, Xiaojuanen
kaust.authorTakahashi, Masateruen
kaust.authorHamdan, Samiren
kaust.authorJoudeh, Luayen
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