title: ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.
abstract: Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer.
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA. Electronic address: batanass@mdanderson.org.
authors.forename: Boyko S
authors.initials: BS
authors.lastname: Atanassov
authors.affiliation: University of Missouri - Kansas City, Kansas City, MO 64110, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Mohan
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Xianjiang
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Kuang
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McIvor
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Li
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: University of Arkansas for Medical Sciences, Biochemistry and Molecular Biology, Little Rock, AR 72205, USA.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Byrum
authors.affiliation: University of Arkansas for Medical Sciences, Biochemistry and Molecular Biology, Little Rock, AR 72205, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Calhoun-Davis
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Koutelou
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
authors.affiliation: University of Arkansas for Medical Sciences, Biochemistry and Molecular Biology, Little Rock, AR 72205, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Workman
authors.affiliation: Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA. Electronic address: sroth@mdanderson.org.
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C527169:ATXN7L3 protein, human; C527171:Eny2 protein, human; D006657:Histones; D014157:Transcription Factors; D013869:Thiolester Hydrolases; D010450:Endopeptidases; D000072017:Deubiquitinating Enzymes; C584444:USP22 protein, mouse; C579193:USP51 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C527170:Usp22 protein, human