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dc.contributor.authorRashid, Fahad
dc.contributor.authorHarris, Paul D.
dc.contributor.authorZaher, Manal
dc.contributor.authorSobhy, Mohamed Abdelmaboud
dc.contributor.authorJoudeh, Luay
dc.contributor.authorYan, Chunli
dc.contributor.authorPiwonski, Hubert Marek
dc.contributor.authorTsutakawa, Susan E
dc.contributor.authorIvanov, Ivaylo
dc.contributor.authorTainer, John A
dc.contributor.authorHabuchi, Satoshi
dc.contributor.authorHamdan, Samir
dc.date.accessioned2017-02-28T12:11:06Z
dc.date.available2017-02-28T12:11:06Z
dc.date.issued2017-02-23
dc.identifier.citationRashid F, Harris PD, Zaher MS, Sobhy MA, Joudeh LI, et al. (2017) Single-molecule FRET unveils induced-fit mechanism for substrate selectivity in flap endonuclease 1. eLife 6. Available: http://dx.doi.org/10.7554/elife.21884.
dc.identifier.issn2050-084X
dc.identifier.doi10.7554/elife.21884
dc.identifier.urihttp://hdl.handle.net/10754/622951
dc.description.abstractHuman flap endonuclease 1 (FEN1) and related structure-specific 5'nucleases precisely identify and incise aberrant DNA structures during replication, repair and recombination to avoid genomic instability. Yet, it is unclear how the 5'nuclease mechanisms of DNA distortion and protein ordering robustly mediate efficient and accurate substrate recognition and catalytic selectivity. Here, single-molecule sub-millisecond and millisecond analyses of FEN1 reveal a protein-DNA induced-fit mechanism that efficiently verifies substrate and suppresses off-target cleavage. FEN1 sculpts DNA with diffusion-limited kinetics to test DNA substrate. This DNA distortion mutually 'locks' protein and DNA conformation and enables substrate verification with extreme precision. Strikingly, FEN1 never misses cleavage of its cognate substrate while blocking probable formation of catalytically competent interactions with noncognate substrates and fostering their pre-incision dissociation. These findings establish FEN1 has practically perfect precision and that separate control of induced-fit substrate recognition sets up the catalytic selectivity of the nuclease active site for genome stability.
dc.description.sponsorshipThe research reported here was supported by King Abdullah University of Science and Technology through core funding to S.M.H. and a Competitive Research Award (CRG3) to S.M.H. and J.A.T, as well as National Science Foundation CAREER award MCB-1149521 and National Institute of Health grant R01GM110387 to I.I. J.A.T. also acknowledges support of a Robert A. Welch Chemistry Chair, the Cancer Prevention and Research Institute of Texas, and the University of Texas System Science and Technology Acquisition and Retention STARs program. Computational resources were provided in part by a National Science Foundation XSEDE allocation CHE110042 and through an allocation at NERSC supported by the U.S. Department of Energy Office of Science contract DE-AC02-05CH11231. The authors declare no competing financial interests.
dc.publishereLife Sciences Publications, Ltd
dc.relation.urlhttps://elifesciences.org/content/6/e21884
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBiochemistry
dc.subjectBiophysics
dc.subjectStructural Biology
dc.titleSingle-molecule FRET unveils induced-fit mechanism for substrate selectivity in flap endonuclease 1
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.identifier.journaleLife
dc.eprint.versionPost-print
dc.contributor.institutionDepartment of Chemistry, Georgia State University, Atlanta, United States.
dc.contributor.institutionLawrence Berkeley National Laboratory, Berkeley, United States.
kaust.personRashid, Fahad
kaust.personHarris, Paul D.
kaust.personZaher, Manal S.
kaust.personSobhy, Mohamed Abdelmaboud
kaust.personJoudeh, Luay
kaust.personPiwonski, Hubert Marek
kaust.personHabuchi, Satoshi
kaust.personHamdan, Samir
refterms.dateFOA2018-06-14T05:04:53Z


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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.