Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function.

Autor: Vazquez-Villasenor I; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Garwood CJ; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Simpson JE; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Heath PR; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Mortiboys H; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Wharton SB; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK.
Jazyk: angličtina
Zdroj: The European journal of neuroscience [Eur J Neurosci] 2021 Nov; Vol. 54 (9), pp. 6987-7005. Date of Electronic Publication: 2021 Oct 07.
DOI: 10.1111/ejn.15466
Abstrakt: Oxidative DNA damage induces changes in the neuronal cell cycle and activates a DNA damage response (DDR) to promote repair, but these processes may be altered under a chronic oxidative environment, leading to the accumulation of unrepaired DNA damage and continued activation of a DDR. Failure to repair DNA damage can lead to apoptosis or senescence, which is characterized by a permanent cell cycle arrest. Increased oxidative stress and accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration, but the effects of persistent DNA damage in neurons are not well characterized. We developed a model of persistent oxidative DNA damage in immortalized post-mitotic neurons in vitro by exposing them to a sublethal concentration of hydrogen peroxide following a 'double stress' protocol and performed a detailed characterization of the neuronal transcriptome using microarray analysis. Persistent DNA damage significantly altered the expression of genes involved in cell cycle regulation, DDR and repair mechanisms, and mitochondrial function, suggesting an active DDR response to replication stress and alterations in mitochondrial electron transport chain. Quantitative polymerase chain reaction (qPCR) and functional validation experiments confirmed hyperactivation of mitochondrial Complex I in response to persistent DNA damage. These changes in response to persistent oxidative DNA damage may lead to further oxidative stress, contributing to neuronal dysfunction and ultimately neurodegeneration.
(© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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