RNA Biology ( IF 4.1 ) Pub Date : 2020-06-21 , DOI: 10.1080/15476286.2020.1779492 Sherif Rashad 1, 2 , Xiaobo Han 1 , Kanako Sato 1 , Eikan Mishima 3 , Takaaki Abe 3, 4, 5 , Teiji Tominaga 1 , Kuniyasu Niizuma 1, 2, 6
tiRNAs are small non-coding RNAs produced when tRNA is cleaved under stress. tRNA methylation modifications has emerged in recent years as important regulators for tRNA structural stability and sensitivity to cleavage and tiRNA generation during stress, however, the specificity and higher regulation of such a process is not fully understood. Alkbh1 is a m1A demethylase that leads to destabilization of tRNA and enhanced tRNA cleavage. We examined the impact of Alkbh1 targeting via gene knockdown or overexpression on B35 rat neuroblastoma cell line fate following stresses and on tRNA cleavage. We show that Alkbh1 impact on cell fate and tRNA cleavage is a stress specific process that is impacted by the demethylating capacity of the cellular stress in question. We also show that not all tRNAs are cleaved equally following Alkbh1 manipulation and stress, and that Alkbh1 KD fails to rescue tRNAs from cleavage following demethylating stresses. These findings shed a light on the specificity and higher regulation of tRNA cleavage and should act as a guide for future work exploring the utility of Alkbh1 as a therapeutic target for cancers or ischaemic insult.
中文翻译:
ALKBH1 对 tRNA 切割和 tiRNA 生成的应激特异性影响。
tiRNA 是 tRNA 在压力下裂解时产生的小非编码 RNA。近年来,tRNA 甲基化修饰已成为 tRNA 结构稳定性以及应激期间切割和 tiRNA 生成敏感性的重要调节因子,然而,这一过程的特异性和更高的调节尚不完全清楚。Alkbh1 是 am 1A去甲基化酶,可导致 tRNA 不稳定并增强 tRNA 切割。我们研究了通过基因敲低或过度表达来靶向 Alkbh1 对 B35 大鼠神经母细胞瘤细胞系应激后命运和 tRNA 裂解的影响。我们发现 Alkbh1 对细胞命运和 tRNA 裂解的影响是一个应激特异性过程,受到相关细胞应激去甲基化能力的影响。我们还表明,并非所有 tRNA 在 Alkbh1 操作和应激后均等裂解,并且 Alkbh1 KD 未能在去甲基化应激后拯救 tRNA 免受裂解。这些发现揭示了 tRNA 切割的特异性和更高的调控,并应为未来探索 Alkbh1 作为癌症或缺血性损伤治疗靶点的工作提供指导。