Dot1 和 H3K79 甲基化的多种功能。
The diverse functions of Dot1 and H3K79 methylation.
机构信息
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
出版信息
Genes Dev. 2011 Jul 1;25(13):1345-58. doi: 10.1101/gad.2057811.
Abstract
DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ∼10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulation, cell cycle regulation, and the DNA damage response. In addition, gene disruption in mice has revealed that mouse DOT1L plays an essential role in embryonic development, hematopoiesis, cardiac function, and the development of leukemia. The involvement of DOT1L enzymatic activity in leukemogenesis driven by a subset of MLL (mixed-lineage leukemia) fusion proteins raises the possibility of targeting DOT1L for therapeutic intervention.
摘要
DOT1（端粒沉默破坏因子；也称为 Kmt4）最初是在芽殖酵母的基因筛选中发现的，该筛选针对的是那些缺失会导致端粒沉默缺陷的基因。大约 10 年前发现 Dot1 和其哺乳动物同源物 DOT1L（DOT1L 样）具有组蛋白 H3 赖氨酸 79 的组蛋白甲基转移酶活性，在鉴定 Dot1/DOT1L 介导的 H3K79 甲基化在转录调控、细胞周期调控和 DNA 损伤反应中的酶活性及其作用方面取得了巨大进展。此外，在小鼠中的基因敲除揭示了小鼠 DOT1L 在胚胎发育、造血、心脏功能和白血病发展中发挥着重要作用。DOT1L 酶活性参与了一组由 MLL（混合谱系白血病）融合蛋白驱动的白血病发生，这增加了针对 DOT1L 进行治疗干预的可能性。
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