Nucleosome Acidic Patch Promotes RNF168- and RING1B/BMI1-Dependent H2AX and H2A Ubiquitination and DNA Damage Signaling

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dc.creatorLeung, Justin W.en
dc.creatorAgarwal, Poonamen
dc.creatorCanny, Marella D.en
dc.creatorGong, Fadeen
dc.creatorRobinson, Aaron D.en
dc.creatorFinkelstein, Ilya J.en
dc.creatorDurocher, Danielen
dc.creatorMiller, Kyle M.en
dc.date.accessioned2014-12-15T17:10:48Zen
dc.date.available2014-12-15T17:10:48Zen
dc.date.issued2014-03-06en
dc.descriptionJustin W. Leung, Poonam Agarwal, Fade Gong, Aaron D. Robison, Ilya J. Finkelstein, Kyle M. Miller, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of Americaen
dc.descriptionJustin W. Leung, Poonam Agarwal, Fade Gong, Aaron D. Robison, Ilya J. Finkelstein, Kyle M. Miller, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, United States of Americaen
dc.descriptionMarella D. Canny, Daniel Durocher, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canadaen
dc.description.abstractHistone ubiquitinations are critical for the activation of the DNA damage response (DDR). In particular, RNF168 and RING1B/BMI1 function in the DDR by ubiquitinating H2A/H2AX on Lys-13/15 and Lys-118/119, respectively. However, it remains to be defined how the ubiquitin pathway engages chromatin to provide regulation of ubiquitin targeting of specific histone residues. Here we identify the nucleosome acid patch as a critical chromatin mediator of H2A/H2AX ubiquitination (ub). The acidic patch is required for RNF168- and RING1B/BMI1-dependent H2A/H2AXub in vivo. The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro. Furthermore, direct perturbation of the nucleosome acidic patch in vivo by the expression of an engineered acidic patch interacting viral peptide, LANA, results in defective H2AXub and RNF168-dependent DNA damage responses including 53BP1 and BRCA1 recruitment to DNA damage. The acidic patch therefore is a critical nucleosome feature that may serve as a scaffold to integrate multiple ubiquitin signals on chromatin to compose selective ubiquitinations on histones for DNA damage signaling.en
dc.description.catalogingnoteEmail: kyle.miller@austin.utexas.eduen
dc.description.departmentMolecular Biosciencesen
dc.description.departmentInstitute for Cellular and Molecular Biologyen
dc.description.sponsorshipThe IJF laboratory was supported by the Welch Foundation (F-1808) and the Cancer Prevention Research Institute of Texas (CPRIT). DD is the Thomas Kierans Chair in Mechanisms of Cancer Development and a Canada Research Chair (Tier 1) in the Molecular Mechanisms of Genome Integrity. The DD laboratory was supported by CIHR grant MOP89754. The research in the KMM laboratory was supported in part by start-up funds from the University of Texas at Austin and from CPRIT (R116). KMM is a CPRIT scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.Filenamejournal.pgen.1004178.pdfen
dc.identifier.citationLeung JW, Agarwal P, Canny MD, Gong F, Robison AD, et al. (2014) Nucleosome Acidic Patch Promotes RNF168- and RING1B/BMI1-Dependent H2AX and H2A Ubiquitination and DNA Damage Signaling. PLoS Genet 10(3): e1004178. doi:10.1371/journal.pgen.1004178en
dc.identifier.doiDOI: 10.1371/journal.pgen.1004178en
dc.identifier.urihttp://hdl.handle.net/2152/27933en
dc.language.isoEnglishen
dc.publisherPLOS Geneticsen
dc.rightsAdministrative deposit of works to UT Digital Repository: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access at http://www.plosgenetics.org. The public license is specified as CC-BY: http://creativecommons.org/licenses/by/4.0/. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.subjectchromatinen
dc.subjectDNA damageen
dc.subjectDNA-binding proteinsen
dc.subjectHistonesen
dc.subjectlasersen
dc.subjectlysineen
dc.subjectnucleosomesen
dc.subjectubiquitinationen
dc.titleNucleosome Acidic Patch Promotes RNF168- and RING1B/BMI1-Dependent H2AX and H2A Ubiquitination and DNA Damage Signalingen
dc.typeArticleen

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