Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, LE1 7RH, UK.
Department of Molecular and Cell Biology, University of Leicester, Leicester, LE1 7RH, UK.
Nat Commun. 2020 Jun 26;11(1):3252. doi: 10.1038/s41467-020-17078-8.
MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
MiDAC 是七个不同的大型多蛋白复合物之一，可将 I 类组蛋白去乙酰化酶募集到基因组以调节基因表达。尽管 MiDAC 涉及细胞周期调控和几种癌症，但对其功能或结构知之甚少。在这里，我们表明 MiDAC 对于癌细胞系有丝分裂过程中的染色体排列很重要。由于基因表达的干扰导致心脏畸形和造血功能衰竭，缺乏 MiDAC 蛋白 DNTTIP1 或 MIDEAS 的小鼠在胚胎晚期会出现相同的表型。这表明 MiDAC 具有重要的独特功能，不能被其他 HDAC 复合物代偿。与此一致的是，MiDAC 的冷冻电镜结构揭示了一种独特而独特的组装方式。四个 HDAC1 拷贝位于外围，具有向外的活性位点，这表明该复合物可能靶向多个核小体，暗示了一种连续的去乙酰化酶功能。
