Ubiquitin accumulation on disease associated protein aggregates is correlated with nuclear ubiquitin depletion, histone De-ubiquitination and impaired DNA damage response

Adi Ben Yehuda, Marwa Risheq, Ofra Novoplansky, Kirill Bersuker, Ron R. Kopito, Michal Goldberg, Michael Brandeis

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageAmerican English
Article numbere0169054
JournalPLoS ONE
Volume12
Issue number1
DOIs
StatePublished - Jan 2017

Bibliographical note

Publisher Copyright:
© 2017 Ben Yehuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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