多梳抑制性去泛素化酶复合物的结构与功能及其在血液肿瘤发生发展中的作用

Structure and Function of the PR-DUB Complex and Its Role in the Development of Haematological Tumours

多梳抑制性去泛素化酶(polycomb repressive deubiquitinase,PR-DUB)复合物是多梳蛋白家族的成员之一,通过调节组蛋白修饰参与染色体的表观遗传修饰。多梳抑制性复合物1(polycomb repressive complex 1,PRC1)和PR-DUB复合物通过对H2AK119Ub泛素化与去泛素化修饰调控平衡,保护活性基因免受异常沉默,去泛素化功能与促进基因活化和建立转录允许的染色质状态有关,除此之外还激活增强子并促进双链断裂处DNA损伤修复。附加性梳样1(additional sex comb-like1,ASXL1)作为表观遗传支架组装染色质修饰复合物和转录因子参与表观遗传调控。BRCA1相关蛋白1(BRCA1-associated protein 1,BAP1)作为去泛素化酶去除底物的泛素化修饰。PR-DUB复合物由核心二聚体和其他辅助因子组成,BAP1与ASXL1形成核心二聚体,其他亚基相互作用调节PR-DUB复合物靶向和功能。ASXL1和BAP1是与PR-DUB复合物去泛素化功能最相关的2个亚基,ASXL1的DEUBAD结构域激活BAP1发挥去泛素化作用水解H2AK119Ub1。了解ASXL1和BAP1的结构以及相互作用机制对研究PR-DUB复合物特异性去泛素化作用的机制至关重要。在人类中,PR-DUB复合物成分的突变经常引起多种血液肿瘤。ASXL 1基因突变常导致蛋白质翻译提前结束,大部分是由于C末端PHD结构域缺失导致。目前认为,PR-DUB复合物中突变的ASXL1或BAP1、表观遗传因子以及Akt/mTOR等靶点或信号通路相互作用是促进血液肿瘤发生发展的可能机制。这对于针对潜在的治疗靶点研究开发新的特异性靶向治疗药物至关重要。本文将介绍PR-DUB复合物的结构与功能、作用机制及其在血液肿瘤疾病中的发生,重点就ASXL1和BAP1进行综述,并系统总结了潜在的靶向治疗药物,以期为PR-DUB复合物在血液疾病防治中的研究提供科学参考。

The polycomb repressive deubiquitinase complex(PR-DUB)is a member of the polycomb group protein involved in the epigenetic modification of chromosomes by regulating histone modifications.The polycomb repressive complex 1(PRC1)and PR-DUB complex protect active genes from aberrant silencing through a balance of ubiquitination and deubiquitination modifications of H2AK119Ub.The deubiquitination function of the PR-DUB complex is associated with the promotion of gene activation and the establishment of transcriptionally permissive chromatin states,in addition to the activation of enhancers and the facilitation of DNA damage repair at double-strand breaks.Additional sex combs-like 1(ASXL1)serves as an epigenetic scaffold for the assembly of chromatin-modifying complexes and transcription factors involved in epigenetic regulation.BRCA1-associated protein 1(BAP1)acts as a deubiquitinating enzyme to remove ubiquitination modification of substrates.The PR-DUB complex consists of a core dimer and other cofactors.BAP1 forms a core dimer with ASXL1,and other subunits interact to regulate the targeting and functioning of the PR-DUB complex.ASXL1 and BAP1 are the two subunits most relevant to the deubiquitination function of the PR-DUB complex,and the DEUBAD domain of ASXL1 activates BAP1 to exert its deubiquitination function to hydrolyze H2AK119Ub1.Understanding the structure and interaction mechanism of ASXL1 and BAP1 is essential to study the mechanism of deubiquitination specific to the PR-DUB complex.In humans,mutations in the components of the PR-DUB complex frequently cause a variety of hematologic neoplasms.Mutations in the ASXL 1 gene often result in premature termination of protein translation,mostly due to the absence of the C-terminal PHD domain.The interaction of mutated ASXL1 or BAP1,epigenetic factors,and targets or signaling pathways such as Akt/mTOR in PR-DUB is now considered as a possible mechanism to promote the development of hematological tumors.This is crucial for the research and development of new specific targeted therapeutic agents against potential therapeutic targets.In this paper,focusing on ASXL1 and BAP1,we will introduce the structure and function of the PR-DUB complex,and its mechanism in the occurrence of hematological tumor diseases,and systematically summarize the potential targeted therapeutic drugs,with a view to providing scientific references for the research of the PR-DUB complex in the prevention and treatment of hematological diseases.