title: Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase.
abstract: Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors.
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO USA.
authors.forename: Mona C
authors.initials: MC
authors.lastname: Majid
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Soll
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Brickner
authors.affiliation: Division of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dango
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO USA mosammaparast@wustl.edu.
authors.forename: Nima
authors.initials: N
authors.lastname: Mosammaparast
mesh_terms: D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D000478:Alkylation / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D053719:Tandem Mass Spectrometry; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*
chemical_list: D049308:Dioxygenases; C486439:ALKBH3 protein, human; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; C486440:ALKBH2 protein, human; D000071499:AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; C000600472:OTUD4 protein, human; D064570:Ubiquitin-Specific Proteases; D045643:DNA Repair Enzymes
keywords: AlkB; DNA repair; alkylation/OTUD4; deubiquitinase