USP11 controls R-loops by regulating senataxin proteostasis.

Cell Line Cellular Senescence / genetics DNA / chemistry DNA Helicases / antagonists & inhibitors DNA-Binding Proteins / genetics Fibroblasts / cytology HEK293 Cells Humans Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors Multifunctional Enzymes / antagonists & inhibitors Nucleic Acid Conformation Promoter Regions, Genetic Protein Isoforms / antagonists & inhibitors Protein Processing, Post-Translational Protein Stability Proteolysis Proteostasis / genetics RNA Helicases / antagonists & inhibitors RNA, Small Interfering / genetics Thiolester Hydrolases / antagonists & inhibitors Ubiquitination

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
15 09 2021
Historique:
received: 03 07 2020
accepted: 05 08 2021
entrez: 16 9 2021
pubmed: 17 9 2021
medline: 7 10 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-25459-w PMID: 34526504 PMC: PMC8443744
pubmed: 34526504
doi: 10.1038/s41467-021-25459-w
pii: 10.1038/s41467-021-25459-w
pmc: PMC8443744
doi:

Substances chimiques

DNA-Binding Proteins 0
KEAP1 protein, human 0
Kelch-Like ECH-Associated Protein 1 0
Multifunctional Enzymes 0
Protein Isoforms 0
RNA, Small Interfering 0
USP11 protein, human 0
xeroderma pigmentosum group F protein 0
DNA 9007-49-2
Thiolester Hydrolases EC 3.1.2.-
SETX protein, human EC 3.6.1.-
DNA Helicases EC 3.6.4.-
RNA Helicases EC 3.6.4.13

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

5156

Subventions

Organisme : Wellcome Trust
ID : 103844
Pays : United Kingdom

Informations de copyright

© 2021. The Author(s).

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Auteurs

Mateusz Jurga (M)

School of Bioscience, Department of Molecular Biology and Biotechnology, The Healthy Lifespan Institute and the Institute of Neuroscience, University of Sheffield, Sheffield, UK.
The Institute of Cancer Therapeutics, University of Bradford, Bradford, UK.

Arwa A Abugable (AA)

School of Bioscience, Department of Molecular Biology and Biotechnology, The Healthy Lifespan Institute and the Institute of Neuroscience, University of Sheffield, Sheffield, UK.

Alastair S H Goldman (ASH)

Faculty of Life Sciences, University of Bradford, Bradford, UK.

Sherif F El-Khamisy (SF)

School of Bioscience, Department of Molecular Biology and Biotechnology, The Healthy Lifespan Institute and the Institute of Neuroscience, University of Sheffield, Sheffield, UK. s.el-khamisy@sheffield.ac.uk.
The Institute of Cancer Therapeutics, University of Bradford, Bradford, UK. s.el-khamisy@sheffield.ac.uk.
ORCID: 0000-0003-2721-7763

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Vieillissement › Vieillissement de la cellule › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Helicase › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Fibroblastes › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéine-1 de type kelch associée à ECH › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Enzymes multifonctionnelles › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Stabilité protéique › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Métabolisme › Protéolyse › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Métabolisme › Homéostasie protéique › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › RNA helicases › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Thiolester hydrolases › USP11 controls R-loops by regulating senataxin...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Ubiquitination › USP11 controls R-loops by regulating senataxin...