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Trimethylation of histone H3K76 by Dot1B enhances cell cycle progression after mitosis in Trypanosoma cruzi.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2020-03-06 , DOI: 10.1016/j.bbamcr.2020.118694
Vinicius Santana Nunes 1 , Nilmar Silvio Moretti 2 , Marcelo Santos da Silva 3 , Maria Carolina Elias 3 , Christian J Janzen 4 , Sergio Schenkman 2
Affiliation  

Dot1 enzymes are histone methyltransferases that mono-, di- and trimethylate lysine 79 of histone H3 to affect several nuclear processes. The functions of these different methylation states are still largely unknown. Trypanosomes, which are flagellated protozoa that cause several parasitic diseases, have two Dot1 homologues. Dot1A catalyzes the mono- and dimethylation of lysine 76 during late G2 and mitosis, and Dot1B catalyzes trimethylation, which is a modification found in all stages of the cell cycle. Here, we generated Trypanosoma cruzi lines lacking Dot1B. Deletion of one allele resulted in parasites with increased levels of mono- and dimethylation and a reduction in H3K76me3. In the full knockout (DKO), no trimethylation was observed. Both the DKO and the single knockout (SKO) showed aberrant morphology and decreased growth due to cell cycle arrest after G2. This phenotype could be rescued by caffeine in the DKO, as caffeine is a checkpoint inhibitor of the cell cycle. The knockouts also phosphorylated γH2A without producing extensive DNA breaks, and Dot1B-depleted cells were more susceptible to general checkpoint kinase inhibitors, suggesting that a lack of H3K76 trimethylation prevents the initiation and/or completion of cytokinesis.

中文翻译:

Dot1B对组蛋白H3K76的三甲基化作用可增强克氏锥虫有丝分裂后的细胞周期进程。

Dot1酶是组蛋白H3的单,二和三甲基赖氨酸79的组蛋白甲基转移酶,可影响多个核过程。这些不同的甲基化状态的功能仍然很大程度上未知。锥虫是引起多种寄生虫病的鞭毛原生动物,具有两个Dot1同源物。Dot1A在晚期G2和有丝分裂期间催化赖氨酸76的单和二甲基化,而Dot1B催化三甲基化,这是在细胞周期所有阶段中发现的一种修饰。在这里,我们生成了缺乏Dot1B的锥虫锥虫线。删除一个等位基因导致寄生虫的单和二甲基化水平增加,H3K76me3减少。在完全敲除(DKO)中,未观察到三甲基化。由于G2后细胞周期停滞,DKO和单敲除(SKO)均显示异常形态并降低了生长。由于咖啡因是细胞周期的关卡抑制剂,因此可以通过DKO中的咖啡因挽救这种表型。敲除基因还可以使γH2A磷酸化,而不会产生大量的DNA断裂,并且耗尽Dot1B的细胞更容易受到一般检查点激酶抑制剂的影响,这表明缺乏H3K76三甲基化会阻止胞质分裂的开始和/或完成。
更新日期:2020-03-19
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