Vazquez‐Villasenor, I., Garwood, C.J., Simpson, J.E. orcid.org/0000-0002-3753-4271 et al. (3 more authors) (2021) Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function. European Journal of Neuroscience, 54 (9). pp. 6987-7005. ISSN 0953-816X
Abstract
Oxidative DNA damage induces changes in the neuronal cell cycle and activates a DNA damage response 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 DNA damage response. 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 sub-lethal 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, DNA damage response and repair mechanisms, and mitochondrial function, suggesting an active DDR response to replication stress and alterations in mitochondrial electron transport chain. 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | oxidative stress; mitochondrial complex I; cell cycle re-entry; DNA damage response; post-mitotic |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/J004308/1 BRITISH NEUROPATHOLOGICAL SOCIETY nan ALZHEIMER'S RESEARCH UK ARUK-PG2019A-003 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 27 Sep 2021 13:06 |
Last Modified: | 15 Mar 2022 11:28 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1111/ejn.15466 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:178513 |