组蛋白H3K79甲基化转移酶DOT1L的功能研究进展

Research progress on the function of histone H3K79 methyltransferase DOT1L

组蛋白赖氨酸甲基化是一种翻译后修饰(Post-translational modification,PTM),调控真核生物的基因表达,其中组蛋白H3第79位赖氨酸(H3K79)的甲基化是一个进化保守的表观遗传标志,与基因转录、细胞周期等生物学过程密切相关.研究发现,DOT1L催化H3K79甲基化,参与胚胎发育及组织系统分化,其异常表达是众多癌症,包括MLL重排(MLL-rearrangement,MLL-r)白血病发生和预后不良的诱因之一.因此,DOT1L成为了多种癌症潜在的治疗靶标,其小分子抑制剂也被开发用于临床.对DOT1L结构和分子调控机制以及生物学功能的进展进行综述,为后续开发新型抗肿瘤药物提供新思路.

Histone lysine methylation is one group of post-translational modifications(PTM)that regulate gene expression in eukaryotes.In particular,the methylated histone H3 lysine 79(H3K79)is an evolutionarily conserved epigenetic marker and play an important role in biological processes such as gene transcriptionandcell cycle.The study showed that DOT1L catalyzes methylation of H3K79,and is involved in embryonic development and multiple tissue formation.It is also found that DOT1L is aberrantly expressed in many cancers,including MLL-rearranged(MLL-r)leukemia,and is one of the major contributing factors for disease progression and poor prognosis.Therefore,several small-molecule inhibitors targeting DOT1L have been developed in clinical trial for treating cancer.Recent progresses of studies on DOT1L,including the mechanism of its regulation and function from the structural and molecular biology perspectives,which may provide novel insights into the new anti-tumor drug development in future.