ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

Boyko S Atanassov; Ryan D Mohan; Xianjiang Lan; Xianghong Kuang; Yue Lu; Kevin Lin; Elizabeth McIvor; Wenqian Li; Ying Zhang; Laurence Florens; Stephanie D Byrum; Samuel G Mackintosh; Tammy Calhoun-Davis; Evangelia Koutelou; Li Wang; Dean G Tang; Alan J Tackett; Michael P Washburn; Jerry L Workman; Sharon Y R Dent

doi:10.1016/j.molcel.2016.03.030

ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth

Mol Cell. 2016 May 19;62(4):558-71. doi: 10.1016/j.molcel.2016.03.030. Epub 2016 Apr 28.

Authors

Boyko S Atanassov¹, Ryan D Mohan², Xianjiang Lan³, Xianghong Kuang⁴, Yue Lu⁴, Kevin Lin⁴, Elizabeth McIvor⁴, Wenqian Li³, Ying Zhang⁵, Laurence Florens⁵, Stephanie D Byrum⁶, Samuel G Mackintosh⁶, Tammy Calhoun-Davis⁴, Evangelia Koutelou⁴, Li Wang⁴, Dean G Tang⁴, Alan J Tackett⁶, Michael P Washburn⁷, Jerry L Workman⁵, Sharon Y R Dent⁸

Affiliations

¹ 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.
² University of Missouri - Kansas City, Kansas City, MO 64110, USA.
³ 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.
⁴ Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, Houston, TX 77030, USA.
⁵ Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
⁶ University of Arkansas for Medical Sciences, Biochemistry and Molecular Biology, Little Rock, AR 72205, USA.
⁷ 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.
⁸ 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.

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.

MeSH terms

Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Proliferation*
Deubiquitinating Enzymes / genetics
Deubiquitinating Enzymes / metabolism*
Endopeptidases / genetics
Endopeptidases / metabolism
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Genotype
HEK293 Cells
Histones / metabolism*
Humans
MCF-7 Cells
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Phenotype
RNA Interference
Signal Transduction
Thiolester Hydrolases / genetics
Thiolester Hydrolases / metabolism
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection
Tumor Burden*
Ubiquitin Thiolesterase
Ubiquitin-Specific Proteases / genetics
Ubiquitin-Specific Proteases / metabolism
Ubiquitination

Substances

ATXN7L3 protein, human
Eny2 protein, human
Histones
Transcription Factors
Thiolester Hydrolases
Endopeptidases
Deubiquitinating Enzymes
USP22 protein, mouse
USP51 protein, human
Ubiquitin Thiolesterase
Ubiquitin-Specific Proteases
Usp22 protein, human

Abstract

MeSH terms

Substances

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