Yes / R-loops are by-products of transcription that must be tightly regulated to maintain genomic
stability and gene expression. Here, we describe a mechanism for the regulation of the Rloop-
specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11
(USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX
K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels
and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via
compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11
reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of
the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1
increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation.
These data define a ubiquitination-dependent mechanism for SETX regulation, which is
controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer
and neurological disease. / Wellcome Trust Investigator Award, Lister Institute of Preventative Medicine Fellowship
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/18592 |
| Date | 15 September 2021 |
| Creators | Jurga, Mateusz, Abugable, A.A., Goldman, Alastair S.H., El-Khamisy, Sherif |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | © 2021 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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. |
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