title: Deubiquitinases as a signaling target of oxidative stress.
abstract: Deubiquitinating enzymes (DUBs) constitute a large family of cysteine proteases that have a broad impact on numerous biological and pathological processes, including the regulation of genomic stability. DUBs are often assembled onto multiprotein complexes to assist in their localization and substrate selection, yet it remains unclear how the enzymatic activity of DUBs is modulated by intracellular signals. Herein, we show that bursts of reactive oxygen species (ROS) reversibly inactivate DUBs through the oxidation of the catalytic cysteine residue. Importantly, USP1, a key regulator of genomic stability, is reversibly inactivated upon oxidative stress. This, in part, explains the rapid nature of PCNA monoubiquitination-dependent DNA damage tolerance in response to oxidative DNA damage in replicating cells. We propose that DUBs of the cysteine protease family act as ROS sensors in human cells and that ROS-mediated DUB inactivation is a critical mechanism for fine-tuning stress-activated signaling pathways.
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Xiomaris M
authors.initials: XM
authors.lastname: Cotto-Rios
authors.forename: Miklós
authors.initials: M
authors.lastname: Békés
authors.forename: Jessica
authors.initials: J
authors.lastname: Chapman
authors.forename: Beatrix
authors.initials: B
authors.lastname: Ueberheide
authors.forename: Tony T
authors.initials: TT
authors.lastname: Huang
mesh_terms: D029681:Arabidopsis Proteins; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D029681:Arabidopsis Proteins; D017382:Reactive Oxygen Species; D057149:Ubiquitinated Proteins; D010450:Endopeptidases; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases