Janzen Christian J, Hake Sandra B, Lowell Joanna E, Cross George A M
Laboratory of Molecular Parasitology, The Rockefeller University, New York, New York 10021, USA.
Mol Cell. 2006 Aug;23(4):497-507. doi: 10.1016/j.molcel.2006.06.027.
DOT1 is an evolutionarily conserved histone H3 lysine 79 (H3K79) methyltransferase. K79 methylation is associated with transcriptional activation, meiotic checkpoint control, and DNA double-strand break (DSB) responses. Trypanosoma brucei has two homologs, DOT1A and DOT1B, which are responsible for dimethylation and trimethylation of H3K76, respectively (K76 in T. brucei is synonymous to K79 in other organisms). K76 dimethylation is only detectable during mitosis, whereas trimethylation occurs throughout the cell cycle. Deletion of DOT1B resulted in dimethylation of K76 throughout the cell cycle and caused subtle defects in cell cycle regulation and impaired differentiation. RNAi-mediated depletion of DOT1A appears to disrupt a mitotic checkpoint, resulting in premature progression through mitosis without DNA replication, generating a high proportion of cells with a haploid DNA content, an unprecedented state for trypanosomes. We propose that DOT1A and DOT1B influence the trypanosome cell cycle by regulating the degree of H3K76 methylation.
DOT1是一种进化上保守的组蛋白H3赖氨酸79（H3K79）甲基转移酶。K79甲基化与转录激活、减数分裂检查点控制以及DNA双链断裂（DSB）反应相关。布氏锥虫有两个同源物，DOT1A和DOT1B，它们分别负责H3K76的二甲基化和三甲基化（布氏锥虫中的K76与其他生物体中的K79同义）。K76二甲基化仅在有丝分裂期间可检测到，而三甲基化在整个细胞周期中都发生。DOT1B的缺失导致整个细胞周期中K76的二甲基化，并在细胞周期调控中引起细微缺陷以及分化受损。RNA干扰介导的DOT1A缺失似乎破坏了一个有丝分裂检查点，导致在没有DNA复制的情况下过早进入有丝分裂，产生高比例单倍体DNA含量的细胞，这是锥虫前所未有的状态。我们提出DOT1A和DOT1B通过调节H3K76甲基化程度来影响锥虫细胞周期。
