Defective repair of topoisomerase I induced chromosomal damage in Huntington’s disease

Abstract

Topoisomerase1 (TOP1)-mediated chromosomal breaks are endogenous sources of DNA damage that affect neuronal genome stability. Whether TOP1 DNA breaks are sources of genomic instability in Huntington’s disease (HD) is unknown. Here, we report defective 53BP1 recruitment in multiple HD cell models, including striatal neurons derived from HD patients. Defective 53BP1 recruitment is due to reduced H2A ubiquitination caused by the limited RNF168 activity. The reduced availability of RNF168 is caused by an increased interaction with p62, a protein involved in selective autophagy. Depletion of p62 or disruption of the interaction between RNAF168 and p62 was sufficient to restore 53BP1 enrichment and subsequent DNA repair in HD models, providing new opportunities for therapeutic interventions. These findings are reminiscent to what was described for p62 accumulation caused by C9orf72 expansion in ALS/FTD and suggest a common mechanism by which protein aggregation perturb DNA repair signaling.

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Item Type:	Article
Authors/Creators:	Palminha, N.M. Dos Santos Souza, C. https://orcid.org/0000-0001-5314-6263 Griffin, J. https://orcid.org/0000-0003-3969-7637 Liao, C. https://orcid.org/0000-0003-4059-108X Ferraiuolo, L. https://orcid.org/0000-0001-9118-5714 El-Khamisy, S.F. https://orcid.org/0000-0003-2721-7763
Copyright, Publisher and Additional Information:	© 2022 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Chromatin ubiquitination; DNA repair; Huntington’s disease; RNF168; TOP1cc; p62/SQSTM1
Dates:	Published: March 2022 Published (online): 28 February 2022 Accepted: 8 February 2022
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield)
Funding Information:	Funder Grant number The Wellcome Trust 103844/Z/14/Z
Depositing User:	Symplectic Sheffield
Date Deposited:	07 Mar 2022 08:36
Last Modified:	07 Mar 2022 08:36
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1007/s00018-022-04204-6
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:184446

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Defective repair of topoisomerase I induced chromosomal damage in Huntington’s disease

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