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dc.contributor.authorLeith, Jason S.
dc.contributor.authorTafvizi, Anahita
dc.contributor.authorHuang, Fang
dc.contributor.authorUspal, William Eric
dc.contributor.authorFersht, Alan R.
dc.contributor.authorOijen, Antoine M. van
dc.contributor.authorDoyle, Patrick S
dc.contributor.authorMirny, Leonid A
dc.date.accessioned2013-02-28T17:10:38Z
dc.date.available2013-02-28T17:10:38Z
dc.date.issued2012-10
dc.date.submitted2011-12
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/77237
dc.description.abstractProper timing of gene expression requires that transcription factors (TFs) efficiently locate and bind their target sites within a genome. Theoretical studies have long proposed that one-dimensional sliding along DNA while simultaneously reading its sequence can accelerate TF’s location of target sites. Sliding by prokaryotic and eukaryotic TFs were subsequently observed. More recent theoretical investigations have argued that simultaneous reading and sliding is not possible for TFs without their possessing at least two DNA-binding modes. The tumor suppressor p53 has been shown to slide on DNA, and recent experiments have offered structural and single molecule support for a two-mode model for the protein. If the model is applicable to p53, then the requirement that TFs be able to read while sliding implies that noncognate sites will affect p53’s mobility on DNA, which will thus be generally sequence-dependent. Here, we confirm this prediction with single-molecule microscopy measurements of p53’s local diffusivity on noncognate DNA. We show how a two-mode model accurately predicts the variation in local diffusivity, while a single-mode model does not. We further determine that the best model of sequence-specific binding energy includes terms for “hemi-specific” binding, with one dimer of tetrameric p53 binding specifically to a half-site and the other binding nonspecifically to noncognate DNA. Our work provides evidence that the recognition by p53 of its targets and the timing thereof can depend on its noncognate binding properties and its ability to change between multiple modes of binding, in addition to the much better-studied effects of cognate-site binding.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1120452109en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleSequence-dependent sliding kinetics of p53en_US
dc.typeArticleen_US
dc.identifier.citationLeith, J. S. et al. “Sequence-dependent Sliding Kinetics of P53.” Proceedings of the National Academy of Sciences 109.41 (2012): 16552–16557. © 2012 National Academy of Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Institute for Medical Engineering & Scienceen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemical Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Physicsen_US
dc.contributor.departmentMassachusetts Institute of Technology. School of Engineeringen_US
dc.contributor.mitauthorUspal, William Eric
dc.contributor.mitauthorDoyle, Patrick S.
dc.contributor.mitauthorMirny, Leonid A.
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsLeith, J. S.; Tafvizi, A.; Huang, F.; Uspal, W. E.; Doyle, P. S.; Fersht, A. R.; Mirny, L. A.; van Oijen, A. M.en
dc.identifier.orcidhttps://orcid.org/0000-0002-0785-5410
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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