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Pseudouridines on Trypanosoma brucei mRNAs are developmentally regulated: Implications to mRNA stability and protein binding
Molecular Microbiology ( IF 3.6 ) Pub Date : 2021-06-24 , DOI: 10.1111/mmi.14774
K Shanmugha Rajan 1 , Katerina Adler 1 , Hava Madmoni 1 , Dana Peleg-Chen 1 , Smadar Cohen-Chalamish 1 , Tirza Doniger 1 , Beathrice Galili 1 , Doron Gerber 1 , Ron Unger 1 , Christian Tschudi 2 , Shulamit Michaeli 1
Affiliation  

The parasite Trypanosoma brucei cycles between an insect and a mammalian host and is the causative agent of sleeping sickness. Here, we performed high-throughput mapping of pseudouridines (Ψs) on mRNA from two life stages of the parasite. The analysis revealed ~273 Ψs, including developmentally regulated Ψs that are guided by homologs of pseudouridine synthases (PUS1, 3, 5, and 7). Mutating the U that undergoes pseudouridylation in the 3′ UTR of valyl-tRNA synthetase destabilized the mRNA level. To investigate the mechanism by which Ψ affects the stability of this mRNA, proteins that bind to the 3′ UTR were identified, including the RNA binding protein RBSR1. The binding of RBSR1 protein to the 3′ UTR was stronger when lacking Ψ compared to transcripts carrying the modification, suggesting that Ψ can inhibit the binding of proteins to their target and thus affect the stability of mRNAs. Consequently, Ψ modification on mRNA adds an additional level of regulation to the dominant post-transcriptional control in these parasites.

中文翻译:

布氏锥虫 mRNA 上的假尿苷受到发育调控:对 mRNA 稳定性和蛋白质结合的影响

寄生虫布氏锥虫在昆虫和哺乳动物宿主之间循环,是昏睡病的病原体。在这里,我们对来自寄生虫两个生命阶段的 mRNA 进行了假尿苷 (Ψs) 的高通量定位。分析揭示了约 273 个 Ψs,包括由假尿苷合酶(PUS1、3、5 和 7)的同源物引导的发育调节的 Ψs。突变在 valyl-tRNA 合成酶的 3' UTR 中经历假尿苷化的 U 使 mRNA 水平不稳定。为了研究 Ψ 影响该 mRNA 稳定性的机制,鉴定了与 3' UTR 结合的蛋白质,包括 RNA 结合蛋白 RBSR1。与携带修饰的转录物相比,当缺乏Ψ时,RBSR1蛋白与3'UTR的结合更强,表明Ψ可以抑制蛋白质与其靶标的结合,从而影响mRNA的稳定性。因此,对 mRNA 的 Ψ 修饰为这些寄生虫的主要转录后控制增加了额外的调节水平。
更新日期:2021-06-24
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