组蛋白甲基转移酶 DOT1L：调控功能和癌症治疗靶点。
The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target.
机构信息
Children's Cancer Institute Australia for Medical Research Randwick NSW 2031, Australia.
Department of Pathology and Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia Kensington NSW 2052, Australia.
出版信息
Am J Cancer Res. 2015 Aug 15;5(9):2823-37. eCollection 2015.
Abstract
DOT1L is a unique histone methyltransferase that targets the histone H3 lysine 79 (H3K79) residue for mono-, di- and tri- methylation. Histone H3K79 mono- and di-methylation results in active gene transcription, while H3K79 tri-methylation is associated with gene repression. DOT1L has a critical role in regulating gene transcription, development, cell cycle progression, somatic reprogramming and DNA damage repair. DOT1L interacts with Mixed Lineage Leukemia (MLL) fusion proteins, leading to enhanced H3K79 methylation, maintenance of open chromatin, overexpression of downstream oncogenes and leukemogenesis. Importantly, small molecule DOT1L inhibitors have been recently developed, and one of the DOT1L inhibitors is already under investigation in a Phase I clinical trial in patients with MLL fusion gene-driven leukemia.
摘要
DOT1L 是一种独特的组蛋白甲基转移酶，它将组蛋白 H3 赖氨酸 79（H3K79）残基作为单、二和三甲基化的靶标。组蛋白 H3K79 的单甲基化和二甲基化导致基因转录活跃，而 H3K79 三甲基化与基因抑制有关。DOT1L 在调节基因转录、发育、细胞周期进程、体细胞重编程和 DNA 损伤修复方面发挥着关键作用。DOT1L 与混合谱系白血病（MLL）融合蛋白相互作用，导致 H3K79 甲基化增强、开放染色质的维持、下游癌基因的过度表达和白血病的发生。重要的是，最近已经开发出了小分子 DOT1L 抑制剂，其中一种 DOT1L 抑制剂已经在一项针对 MLL 融合基因驱动的白血病患者的 I 期临床试验中进行研究。
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Nat Commun. 2015 Jul 22;6:7821. doi: 10.1038/ncomms8821.
2
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3
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