title: CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression.
abstract: CUL4B, a scaffold protein that assembles the CRL4B ubiquitin ligase complex, participates in the regulation of a broad spectrum of biological processes. Here, we demonstrate a crucial role of CUL4B in driving cell cycle progression. We show that loss of CUL4B results in a significant reduction in cell proliferation and causes G1 cell cycle arrest, accompanied by the upregulation of the cyclin-dependent kinase (CDK) inhibitors (CKIs) p21 and p57 (encoded by CDKN1A and CDKN1C, respectively). Strikingly, CUL4B was found to negatively regulate the function of p21 through transcriptional repression, but not through proteolysis. Furthermore, we demonstrate that CRL4B and SIN3A-HDAC complexes interact with each other and co-occupy the CDKN1A and CDKN1C promoters. Lack of CUL4B led to a decreased retention of SIN3A-HDAC components and increased levels of acetylated H3 and H4. Interestingly, the ubiquitylation function of CRL4B is not required for the stable retention of SIN3A-HDAC on the promoters of target genes. Thus, in addition to directly contributing to epigenetic silencing by catalyzing H2AK119 monoubiquitylation, CRL4B also facilitates the deacetylation function of SIN3A-HDAC. Our findings reveal a coordinated action between CRL4B and SIN3A-HDAC complexes in transcriptional repression.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Liangqian
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China yxg8@sdu.edu.cn.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: C517832:CUL4B protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: CDKN1A; CRL4B; Cell cycle progression; SIN3A-HDAC