MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer.
MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer.
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DOI：
10.1186/s13059-022-02776-x
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发表时间：
2022-09-30
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
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brca1相关蛋白1 （BAP1）是一种泛素羧基末端水解酶，与不同的表观遗传因子如ASXL1-3、FOXK1/2形成多蛋白复合物。在染色质水平上，BAP1与该复合物内的其他亚基合作，催化组蛋白H2AK119上的单泛素化去除，并在哺乳动物细胞中作为转录激活因子发挥作用。然而，不同亚基之间的串扰以及这些亚基如何影响BAP1的功能仍不清楚。我们报道了甲基- cpg结合结构域蛋白5和6 （MBD5和MBD6）的鉴定，它们与大支架亚基ASXL1-3的c端PHD指结合，并在染色质上稳定BAP1复合物。我们进一步鉴定了一种新的果蝇蛋白，六条带（SBA），作为人类MBD5和MBD6的同源物，并证明了BAP1复合物的核心模块在结构和功能上从果蝇（Calypso/ASX/SBA）到人类细胞（BAP1/ASXL/MBD）是保守的。BAP1复合体的功能障碍是由其亚基的错误调控/突变引起的，在许多人类癌症中很常见。在bap1依赖性的人类癌症中，如小细胞肺癌（SCLC）， MBD6往往是形成的主要复合体的一部分。因此，MBD6的缺失导致BAP1在染色质上占据的全局缺失，从而导致BAP1依赖基因表达的减少和体外和体内肿瘤生长的减少。我们将MBD5和MBD6描述为BAP1复合体的重要调节因子，并维持其转录格局，揭示了靶向MBD5和MBD6治疗BAP1依赖性人类癌症的潜力。在线版本包含补充材料，可在10.1186/s13059-022-02776-x获得。
BRCA1-associated protein 1 (BAP1) is an ubiquitin carboxy-terminal hydrolase, which forms a multi-protein complex with different epigenetic factors, such as ASXL1-3 and FOXK1/2. At the chromatin level, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex and functions as a transcriptional activator in mammalian cells. However, the crosstalk between different subunits and how these subunits impact BAP1’s function remains unclear. We report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at the chromatin. We further identify a novel Drosophila protein, the six-banded (SBA), as an ortholog of human MBD5 and MBD6, and demonstrate that the core modules of the BAP1 complex is structurally and functionally conserved from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in its subunit(s) are frequent in many human cancers. In BAP1-dependent human cancers, such as small cell lung cancer (SCLC), MBD6 tends to be a part of the predominant complex formed. Therefore, depletion of MBD6 leads to a global loss of BAP1 occupancy at the chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. We characterize MBD5 and MBD6 as important regulators of the BAP1 complex and maintain its transcriptional landscape, shedding light on the therapeutic potential of targeting MBD5 and MBD6 in BAP1-dependent human cancers. The online version contains supplementary material available at 10.1186/s13059-022-02776-x.
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影响因子：
10.5
作者：
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