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CRL4B Interacts with and Coordinates the SIN3A-HDAC Complex To ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 4679–4691 doi:10.1242/jcs.154245 RESEARCH ARTICLE CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression Qinghong Ji, Huili Hu, Fan Yang, Jupeng Yuan, Yang Yang, Liangqian Jiang, Yanyan Qian, Baichun Jiang, Yongxin Zou, Yan Wang, Changshun Shao and Yaoqin Gong* ABSTRACT Shahbazian and Grunstein, 2007). HATs catalyze the acetylation of histones and other proteins, whereas HDACs catalyze the CUL4B, a scaffold protein that assembles the CRL4B ubiquitin removal of the acetyl moieties from acetylated proteins. To date, ligase complex, participates in the regulation of a broad spectrum of 18 mammalian HDAC isoforms have been characterized and are biological processes. Here, we demonstrate a crucial role of CUL4B classified into class I, class II, class III and class IV (de Ruijter in driving cell cycle progression. We show that loss of CUL4B et al., 2003). Among them, HDAC1 and HDAC2, members of results in a significant reduction in cell proliferation and causes G1 class I, represent two of the best-characterized HDACs to date. cell cycle arrest, accompanied by the upregulation of the cyclin- They function in a number of deacetylase complexes – including dependent kinase (CDK) inhibitors (CKIs) p21 and p57 (encoded by SIN3A-HDAC, NuRD-HDAC, the BCH10-containing complex CDKN1A and CDKN1C, respectively). Strikingly, CUL4B was found and the CoREST-HDAC complex – and they are generally to negatively regulate the function of p21 through transcriptional associated with transcriptional repression (Hayakawa and repression, but not through proteolysis. Furthermore, we Nakayama, 2011; Laherty et al., 1997; Wang et al., 2009b). demonstrate that CRL4B and SIN3A-HDAC complexes interact Cells lacking both HDAC1 and HDAC2 show G1 cell cycle arrest with each other and co-occupy the CDKN1A and CDKN1C accompanied by upregulation of the cyclin-dependent kinase promoters. Lack of CUL4B led to a decreased retention of SIN3A- (CDK) inhibitors (CKIs) p21 and p57 (encoded by CDKN1A and HDAC components and increased levels of acetylated H3 and H4. CDKN1C, respectively) (Gui et al., 2004; Wilting et al., 2010; Interestingly, the ubiquitylation function of CRL4B is not required for Yamaguchi et al., 2010; Zupkovitz et al., 2010). the stable retention of SIN3A-HDAC on the promoters of target Cullin 4 (CUL4) acts as the scaffold of the E3 ligase complex genes. Thus, in addition to directly contributing to epigenetic CRL4. By interaction (at its C-terminal end) with a small RING silencing by catalyzing H2AK119 monoubiquitylation, CRL4B also finger protein [either ROC1 (also known as RBX1) or ROC2 facilitates the deacetylation function of SIN3A-HDAC. Our findings (also known as RBX2)], CUL4 recruits the E2 ubiquitin- reveal a coordinated action between CRL4B and SIN3A-HDAC conjugating enzyme (E2) charged with a ubiquitin ready for complexes in transcriptional repression. transfer to the substrate (Jackson and Xiong, 2009). The N- terminal domain of CUL4 binds to the substrate adaptor DNA KEY WORDS: CRL4B, CDKN1A, SIN3A-HDAC, Cell cycle damage binding protein 1 (DDB1), which recruits various progression substrate-recognition proteins (DCAF proteins), resulting in a large family of distinct CRL4 E3 ubiquitin ligase complexes INTRODUCTION (Higa et al., 2006; Lee and Zhou, 2007; Scott et al., 2006). CRL4 Histones are subject to a variety of post-translational targets different substrates for proteasomal degradation or for modifications that affect chromatin configuration, transcription protein modification, and thus regulates a broad variety of and the DNA damage response (Berger, 2007; Iizuka and Smith, physiologically and developmentally controlled processes (Higa 2003; van Attikum and Gasser, 2009). These modifications and Zhang, 2007). Although earlier studies focused on the include phosphorylation, methylation, acetylation, ubiquitylation redundant function and common substrates of members of the and sumoylation (Peterson and Laniel, 2004; Tan et al., 2011). CUL4 family, CUL4B has been recently reported to function Acetylation of histones, occurring mostly at lysine residues on the distinctly from CUL4A in transcriptional repression, neuronal N-terminal tails of histones H3 and H4, is linked to the opening of gene regulation, response to reactive oxygen species (ROS) and chromatin and activation of gene expression, either through microRNA regulation (Hu et al., 2012; Li et al., 2011; Nakagawa altering the affinity of histones for DNA or by creating binding and Xiong, 2011; Zou et al., 2013). Although CUL4A has been sites for the proteins that regulate chromatin accessibility. The proved to regulate the cell cycle by targeting CDT1 and CKIs antagonistic activities of two types of enzymes, histone such as p21 and p27 (encoded by CDKN1B) for proteolysis in acetyltransferases (HATs) and histone deacetylases (HDACs), cultured cells, it seems to be dispensable for embryonic control the reversible acetylation state (Kuo and Allis, 1998; development (Abbas et al., 2008; Hu et al., 2004; Li et al., 2006). However, studies from three independent groups have Key Laboratory of Experimental Teratology, Ministry of Education, Institute of demonstrated that Cul4b-null embryos are impaired in Molecular Medicine and Genetics, Shandong University School of Medicine, development (Chen et al., 2012; Jiang et al., 2012; Liu et al., Jinan, 250012, China. 2012), yet the underlying mechanisms still need to be elucidated. *Author for correspondence ([email protected]) Moreover, recent studies have established CRL4, especially CRL4B, as important epigenetic regulators. CUL4B ablation Received 1 April 2014; Accepted 16 August 2014 could block the degradation of WDR5, a core subunit of the Journal of Cell Science 4679 RESEARCH ARTICLE Journal of Cell Science (2014) 127, 4679–4691 doi:10.1242/jcs.154245 histone H3 lysine 4 (H3K4) methyltransferase complex, and thus encodes p21, was 2.3-fold higher in Cul4b-null MEFs than in increase H3K4 trimethylation (H3K4me3) on some neuronal gene wild-type MEFs (Fig. 2B, upper panel), and the CDKN1A mRNA promoters, leading to their upregulation (Nakagawa and Xiong, levels were 2.0-fold and 1.8-fold higher in CUL4B-knockdown 2011). Recently, we have shown that CRL4B functions as a HEK293 and HeLa cells (Fig. 2B, middle and lower panels), transcriptional co-repressor of tumor suppressors by respectively, suggesting that CUL4B might repress CDKN1A monoubiquitylating H2AK119 and coordinating with either the expression at the transcriptional level. Given that CDKN1A is a PRC2 complex or with DNA methyltransferase, HP1 and major transcriptional target of p53, we next examined whether the SUV39H1 to regulate histone methylation or DNA methylation increased transcription of CDKN1A was due to increased (Hu et al., 2012; Yang et al., 2013). Here, we show that CUL4B activation of p53 in CUL4B-deficient cells. Western blotting depletion can inhibit cell proliferation owing to the upregulation and qRT-PCR assays showed that there was no difference in the of Cdkn1a and Cdkn1c. Importantly, we demonstrate that the level of p53 in CUL4B-deficient cells as compared with that of CRL4B complex interacts and coordinates with SIN3A-HDAC to controls (Fig. 2C), suggesting that the basal (stress-free) exert its repressive effect. upregulation of p21 is independent of p53. We also demonstrated that the negative effect of CUL4B on the p21 RESULTS level was not due to CUL4B-mediated protein degradation, Lack of CUL4B inhibits cell proliferation in MEFs because treatment with the proteasome inhibitor MG132 did not Our previous results have shown that reduced cell proliferation narrow the difference between CUL4B-overexpressing and and increased apoptosis can lead to developmental arrest in control cells (Fig. 2D). Furthermore, examination of p21 decay Cul4b-null embryos (Jiang et al., 2012). We also noted that rates, performed by adding cycloheximide to the culture medium CUL4B-deficient cells are severely selected against in vivo in to inhibit new protein synthesis, did not reveal a significant human and mouse heterozygotes (Jiang et al., 2012; Zou et al., difference between CUL4B-knockdown and control cells 2007). To further understand the mechanism by which CUL4B (Fig. 2E). Taken together, these results demonstrate that regulates cell survival during embryonic development, we CUL4B might function to repress the basal transcription of generated viable Cul4b-null mice by crossing Cul4b-floxed CDKN1A. mice to Sox2-cre transgenic mice, and we then prepared wild- To determine whether the compromised proliferation observed type and Cul4b-null murine embryonic fibroblasts (MEFs), which in CUL4B-deficient cells was mediated by the upregulation of are designated as Cul4bf/Y and Cul4b-/Y, respectively. As shown in p21, we performed rescue experiments in which we transfected Fig. 1A, no CUL4B protein was detected in Cul4b-/Y MEFs, Cul4b-/Y MEFs with siRNA targeting Cdkn1a or with control whereas CUL4A was detected at comparable levels between siRNA. As shown in Fig. 2F and supplementary material Fig. S1, Cul4bf/Y and Cul4b-/Y MEFs. To determine whether the two types knockdown of Cdkn1a could partially rescue the proliferation of MEFs have differential proliferation, we seeded equal numbers defects caused by CUL4B depletion, supporting the idea that of Cul4bf/Y and Cul4b-/Y MEFs onto replicate plates and CUL4B promotes cell proliferation at
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