{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CUL4B is a multifunctional scaffold protein that assembles a specific Cullin‐RING ubiquitin ligase (CRL4B) complex to direct the ubiquitination and subsequent proteasomal degradation of key substrates, thereby regulating diverse cellular processes. In the nervous system, CUL4B targets proteins such as WDR5 to modulate histone H3K4 methylation and neuronal gene expression; mutations in CUL4B are associated with X‐linked mental retardation and impaired neurite outgrowth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In addition, CUL4B forms complexes with the dioxin receptor (AhR) to catalyze ligand‐dependent degradation of sex steroid receptors, illustrating a role for CRL4B in non‐genomic fat‐soluble ligand signaling (1). Beyond development, CUL4B contributes to cell cycle regulation by targeting cyclin E for degradation; its deficiency leads to cyclin E accumulation, prolonged S phase, and impaired cell proliferation, as shown by defects in embryonic development and placental organization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " Moreover, CUL4B plays a distinctive role in nucleotide excision repair by forming a DDB1–CUL4B(DDB2) complex that efficiently monoubiquitinates histone H2A at sites of UV‐induced DNA damage, thereby facilitating chromatin remodeling and DNA lesion processing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In cancer, CUL4B associates with epigenetic regulators—including Polycomb repressive complex components, SUV39H1, HP1, and DNMT3A—to promote histone modifications (H2AK119 monoubiquitination and H3K9 trimethylation) and DNA methylation, thus silencing tumor suppressor genes and enhancing oncogenic phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, through interactions with factors such as SIRT7, CRL4B is also implicated in metabolic regulation by modulating the stability of key nuclear receptors involved in lipid homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies underscore the central role of CUL4B in proteolytic control, epigenetic regulation, cell cycle progression, DNA repair, and metabolic signaling—a convergence of functions that is critical for normal development and whose dysregulation may drive human disease and tumorigenesis (see also."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Patrick S Tarpey, F Lucy Raymond, Sarah O'Meara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/511134"}], "href": "https://doi.org/10.1086/511134"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17236139"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17236139"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yongxin Zou, Qiji Liu, Bingxi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/512489"}], "href": "https://doi.org/10.1086/512489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17273978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17273978"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tadashi Nakagawa, Yue Xiong "}, {"type": "b", "children": [{"type": "t", "text": "X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2011.05.033"}], "href": "https://doi.org/10.1016/j.molcel.2011.05.033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21816345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21816345"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Leigh Ann Higa, Xiaoming Yang, Jianyu Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.5.1.2266"}], "href": "https://doi.org/10.4161/cc.5.1.2266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16322693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16322693"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yongxin Zou, Jun Mi, Jinpeng Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of nuclear localization signal in the N terminus of CUL4B and its essential role in cyclin E degradation and cell cycle progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.050427"}], "href": "https://doi.org/10.1074/jbc.M109.050427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19801544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19801544"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Baichun Jiang, Wei Zhao, Jupeng Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0037070"}], "href": "https://doi.org/10.1371/journal.pone.0037070"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22606329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22606329"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jennifer Guerrero-Santoro, Maria G Kapetanaki, Ching L Hsieh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-6162"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-6162"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18593899"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18593899"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Huili Hu, Yang Yang, Qinghong Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2012.10.024"}], "href": "https://doi.org/10.1016/j.ccr.2012.10.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23238014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23238014"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Y Yang, R Liu, R Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2013.522"}], "href": "https://doi.org/10.1038/onc.2013.522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24292684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24292684"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Tatsuya Yoshizawa, Md Fazlul Karim, Yoshifumi Sato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2014.03.006"}], "href": "https://doi.org/10.1016/j.cmet.2014.03.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24703702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24703702"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Puneet Sharma, Alo Nag "}, {"type": "b", "children": [{"type": "t", "text": "CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Open Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1098/rsob.130217"}], "href": "https://doi.org/10.1098/rsob.130217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24522884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24522884"}]}]}]}