title: The SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein.
abstract: Chromatin-modifying enzymes play a fundamental role in regulating chromatin structure so that DNA replication is spatially and temporally coordinated. For example, the lysine demethylase 4A/Jumonji domain-containing 2A (KDM4A/JMJD2A) is tightly regulated during the cell cycle. Overexpression of JMJD2A leads to altered replication timing and faster S phase progression. In this study, we demonstrate that degradation of JMJD2A is regulated by the proteasome. JMJD2A turnover is coordinated through the SKP1-Cul1-F-box ubiquitin ligase complex that contains cullin 1 and the F-box and leucine-rich repeat protein 4 (FbxL4). This complex interacted with JMJD2A. Ubiquitin overexpression restored turnover and blocked the JMJD2A-dependent faster S phase progression in a cullin 1-dependent manner. Furthermore, increased ubiquitin levels decreased JMJD2A occupancy and BrdU incorporation at target sites. This study highlights a finely tuned mechanism for regulating histone demethylase levels and emphasizes the need to tightly regulate chromatin modifiers so that the cell cycle occurs properly.
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Tarek
authors.initials: T
authors.lastname: Abbas
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Andrew
authors.initials: A
authors.lastname: Allen
authors.affiliation: Department of Biology, Western Kentucky University, Bowling Green, Kentucky 42101-1078.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Rinehart
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129. Electronic address: jwhetstine@hms.harvard.edu.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle; D002843:Chromatin / Q000737:chemistry; D044842:Cullin Proteins / Q000737:chemistry; D004261:DNA Replication; D044783:F-Box Proteins / Q000737:chemistry*; D056466:Histone Demethylases / Q000737:chemistry; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*
chemical_list: D002843:Chromatin; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C561936:FbxL4 protein, human