title: The stability of histone acetyltransferase general control non-derepressible (Gcn) 5 is regulated by Cullin4-RING E3 ubiquitin ligase.
abstract: Histone acetyltransferases play important roles in the regulation of chromatin structure and gene transcription. As one of the most important histone acetyltransferases, general control non-derepressible (Gcn) 5 has been linked to diverse cellular processes and tumorigenesis as well. We have recently identified a functional link between Gcn5 and acidic nucleoplasmic DNA-binding protein 1 (And-1) that is elevated in multiple cancer cells and is essential for Gcn5 protein stability. However, the mechanism by which And-1 regulates Gcn5 protein stability remains unknown. Here we show that the ablation of Cullin4-RING E3 ubiquitin ligase (CRL4) leads to the stabilization of Gcn5 in cells with depleted And-1, and Cdc10-dependent transcript 2 (Cdt2) serves as a substrate receptor protein of CRL4. Overexpression of Cdt2 reduces the Gcn5 protein levels, and CRL(Cdt2) is sufficient to ubiquitinate Gcn5 both in vivo and in vitro. And-1 stabilizes Gcn5 by impairing the interaction between Gcn5 and CRL(Cdt2) and thereby preventing Gcn5 ubiquitination and degradation. The degradation of Gcn5 is not dependent on proliferating cell nuclear antigen, an important player involved in CRL(Cdt2)-mediated protein degradation. Thus, CRL(Cdt2) and And-1 play an essential role in the regulation of Gcn5 protein stability. This study provides us with the mechanistic basis to develop alternative approaches to inhibit Gcn5 activity for cancer therapy.
authors: Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, D. C. 20037.
authors: Yongming
authors: Y
authors: Li
authors: Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, D. C. 20037.
authors: Aimee
authors: A
authors: Jaramillo-Lambert
authors: Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, D. C. 20037.
authors: Jing
authors: J
authors: Hao
authors: Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, D. C. 20037.
authors: Yi
authors: Y
authors: Yang
authors: Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, D. C. 20037. Electronic address: bcmwxz@gwumc.edu.
authors: Wenge
authors: W
authors: Zhu
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C429530:DTL protein, human; C544202:WDHD1 protein, human