title: Ubiquitin Accumulation on Disease Associated Protein Aggregates Is Correlated with Nuclear Ubiquitin Depletion, Histone De-Ubiquitination and Impaired DNA Damage Response.
abstract: Deposition of ubiquitin conjugates on inclusion bodies composed of protein aggregates is a definitive cytopathological hallmark of neurodegenerative diseases. We show that accumulation of ubiquitin on polyQ IB, associated with Huntington's disease, is correlated with extensive depletion of nuclear ubiquitin and histone de-ubiquitination. Histone ubiquitination plays major roles in chromatin regulation and DNA repair. Accordingly, we observe that cells expressing IB fail to respond to radiomimetic DNA damage, to induce gamma-H2AX phosphorylation and to recruit 53BP1 to damaged foci. Interestingly ubiquitin depletion, histone de-ubiquitination and impaired DNA damage response are not restricted to PolyQ aggregates and are associated with artificial aggregating luciferase mutants. The longevity of brain neurons depends on their capacity to respond to and repair extensive ongoing DNA damage. Impaired DNA damage response, even modest one, could thus lead to premature neuron aging and mortality.
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Ben Yehuda
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
authors.forename: Marwa
authors.initials: M
authors.lastname: Risheq
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Novoplansky
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Kirill
authors.initials: K
authors.lastname: Bersuker
authors.affiliation: Department of Biology, Stanford University, Stanford, California, United States of America.
authors.forename: Ron R
authors.initials: RR
authors.lastname: Kopito
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
authors.affiliation: The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Brandeis
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D006657:Histones; D010455:Peptides; D066329:Protein Aggregates; D025801:Ubiquitin; C097188:polyglutamine