Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B.
Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B.
复制标题
Cullin E3连接酶支架蛋白Cul4a和Cul4b的独特和重叠功能。
DOI：
10.1016/j.gene.2015.08.064
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发表时间：
2015-11-15
期刊：
影响因子：
3.5
通讯作者：
Zhou P
中科院分区：
文献类型：
--
作者：
Hannah J;Zhou P
cullin 4基因亚家族包括CUL 4A和CUL 4 B，它们除了CUL 4 B中延长的N-末端区域之外，共享大部分相同的氨基酸序列。两者都充当模块化cullin RING连接酶4（CRL 4）复合物的支架蛋白，其促进多种底物的泛素化。CRL 4功能对细胞至关重要，因为这两种基因或其共享底物衔接蛋白DDB 1的缺失会停止增殖并最终导致细胞死亡。由于它们的高度结构相似性，CUL 4A和CUL 4 B在功能上共享大量重叠。然而，在某些情况下，亚细胞定位，时空表达模式和应力诱导的差异排除功能补偿。本文综述了CUL 4基因在DNA修复和复制、染色质重塑、细胞周期调控、胚胎发生、造血和精子发生等方面的重要功能。CUL 4基因也具有临床相关性，因为失调可能导致癌症的发生，并且CRL 4复合物通常被某些病毒劫持以促进病毒复制和存活。此外，CUL 4 B的突变与患有综合征性X连锁智力残疾（AKA精神发育迟滞）的患者亚组有关。有趣的是，免疫调节药物的抗肿瘤作用是由它们与CRL 4CRBN复合物结合并将E3连接酶重定向至Ikaros转录因子IKZF 1和IKZF 3引起的。由于其对关键细胞功能的影响以及与人类疾病的相关性，CRL 4被认为是治疗干预的有希望的靶点。
The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention.
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