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USP11 controls R-loops by regulating senataxin proteostasis
Jurga, Mateusz Abugable, A.A. Goldman, Alastair S.H.
Jurga, Mateusz
Abugable, A.A.
Goldman, Alastair S.H.
Publication Date
2021
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openAccess
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2021-08-05
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Abstract
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.
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Citation
Jurga M, Abugable AA, Goldman ASH et al (2021) USP11 controls R-loops by regulating senataxin proteostasis. Nature Communications. 12: 5156.
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