Ben Yehuda Adi, Risheq Marwa, Novoplansky Ofra, Bersuker Kirill, Kopito Ron R, Goldberg Michal, Brandeis Michael
The Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Safra Campus, Jerusalem, Israel.
Department of Biology, Stanford University, Stanford, California, United States of America.
PLoS One. 2017 Jan 4;12(1):e0169054. doi: 10.1371/journal.pone.0169054. eCollection 2017.
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.
泛素缀合物在由蛋白质聚集体组成的包涵体上的沉积是神经退行性疾病明确的细胞病理学标志。我们发现，与亨廷顿舞蹈病相关的泛素在多聚谷氨酰胺包涵体上的积累与细胞核泛素的大量消耗以及组蛋白去泛素化相关。组蛋白泛素化在染色质调控和DNA修复中起主要作用。因此，我们观察到表达包涵体的细胞对拟放射性DNA损伤无反应，无法诱导γ-H2AX磷酸化，也不能将53BP1招募至损伤位点。有趣的是，泛素消耗、组蛋白去泛素化以及受损的DNA损伤反应并不局限于多聚谷氨酰胺聚集体，还与人工聚集的荧光素酶突变体有关。脑神经元的寿命取决于它们对广泛持续的DNA损伤做出反应和修复的能力。因此，即使是适度的DNA损伤反应受损也可能导致神经元过早衰老和死亡。
