TY - JOUR
T1 - Ubiquitin accumulation on disease associated protein aggregates is correlated with nuclear ubiquitin depletion, histone De-ubiquitination and impaired DNA damage response
AU - Yehuda, Adi Ben
AU - Risheq, Marwa
AU - Novoplansky, Ofra
AU - Bersuker, Kirill
AU - Kopito, Ron R.
AU - Goldberg, Michal
AU - Brandeis, Michael
N1 - 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.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85008419630&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0169054
DO - 10.1371/journal.pone.0169054
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C2 - 28052107
AN - SCOPUS:85008419630
SN - 1932-6203
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e0169054
ER -
