Journal Article

USP11 controls R-loops by regulating senataxin proteostasis

Jurga, Mateusz, Goldman, Alastair S. H., Abugable, Arwa A., El-Khamisy, Sherif F.

2021

Overview

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 R-loop-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. DNA:RNA hybrids (R-loops) are products of transcription that impact genome integrity and gene expression. Here the authors reveal a mechanism for regulating R-loops in a ubiquitination-dependent manner controlled by the activities of USP11 and KEAP1

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/44 / 13/89 / 14 / 14/19 / 14/63 / 38 / 38/23 / 631/208/211 / 631/80/103 / 631/80/83 / Accumulation / Aging / Cell Line / Cellular Senescence - genetics / Deoxyribonucleic acid / Depletion / DNA / DNA - chemistry / DNA - genetics / DNA - metabolism / DNA helicase / DNA Helicases - antagonists & inhibitors / DNA Helicases - genetics / DNA Helicases - metabolism / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Endonuclease / Fibroblasts - cytology / Fibroblasts - metabolism / Gene expression / HEK293 Cells / Humanities and Social Sciences / Humans / Hybrids / Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors / Kelch-Like ECH-Associated Protein 1 - genetics / Kelch-Like ECH-Associated Protein 1 - metabolism / multidisciplinary / Multifunctional Enzymes - antagonists & inhibitors / Multifunctional Enzymes - genetics / Multifunctional Enzymes - metabolism / Neurological diseases / Nucleic Acid Conformation / Peptidase / Peptidases / Promoter Regions, Genetic / Protein Isoforms - antagonists & inhibitors / Protein Isoforms - genetics / Protein Isoforms - metabolism / Protein Processing, Post-Translational / Protein Stability / Protein turnover / Proteolysis / Proteostasis - genetics / R-loops / RNA Helicases - antagonists & inhibitors / RNA Helicases - genetics / RNA Helicases - metabolism / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Thiolester Hydrolases - antagonists & inhibitors / Thiolester Hydrolases - genetics / Thiolester Hydrolases - metabolism / Transcription / Ubiquitin / Ubiquitin-protein ligase / Ubiquitination