Chemical Modifications to Wobble Uridines in tRNA Regulate Responses to Stress

tRNA 中摆动尿苷的化学修饰可调节应激反应

基本信息

  • 批准号:
    10387039
  • 负责人:
  • 金额:
    $ 35.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-08 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

Abstract Cells respond to environmental stresses by regulating gene expression. Recent studies have demonstrated that stress promotes changes in the levels of enzyme-modified nucleosides found in the anticodon of many tRNAs, to regulate the translation of stress-response transcripts with specific codon usage patterns. In bacteria the wobble U34 residue of tRNA can be enzymatically modified by writers to generate thiolation, geranylation or selenation products at position 2, as well as distinct modifications to position 5, to produce 12 different modified uridines, with many predicted to play key roles in translation and stress responses. The Mnm cluster enzymes can catalyze the formation of these modified uridines and due to their uniqueness to bacteria and the importance of corresponding wobble uridines in the stress response, we propose that they can be exploited to develop technology to tag modified RNA. We have used chemical biology and structural studies to demonstrate that 2-thiouridine (s2U), geranyl-2-thiouridine (ges2U) and seleno-2-thiouridine (se2U) have different base pairing specificity. In addition, using codon analytics of all E. coli genes, we have identified codon-biased transcripts that could be translationally regulated by s2U, ges2U and se2U modifications. We have also shown that cells deficient in the wobble U modifying enzymes MnmE and MnmH are sensitive to killing by chloramphenicol (CAM) and have perturbed translation. We hypothesize that s2U, ges2U and se2U modification levels change in response to environmental stress, to regulate the translation of response proteins. In this application, we will synthesize and characterize 9 wobble modifications linked to MnmE and MnmH. Further, we propose to characterize stress-induced changes in Mnm linked tRNA modifications and determine if translation elongation of codon specific transcripts is linked to one of the 12 uridine tRNA modifications. In addition, we will develop MnmH-based molecular tools to tag and visualize thiolated tRNAs in yeast and human cells. The proposed studies are significant, as they will define a new form of translational regulation in bacteria, generate new reagents and technologies for tagging epitranscriptomic marks and will provide a unified understanding of the 12 different wobble uridines in bacterial tRNA.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Thomas J Begley其他文献

226 - Alkbh8-Dependent Translational Control of Selenoprotein Synthesis and the Senescence Associated Secretory Phenotype (SASP)
  • DOI:
    10.1016/j.freeradbiomed.2015.10.271
  • 发表时间:
    2015-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    May Y Lee;Andrea Leonardi;Akshaya Chandrasekaran;Thomas J Begley;Juan Andres Melendez
  • 通讯作者:
    Juan Andres Melendez
254 - Cross Platform Environmental and Biological Analysis of Model CMP Slurries
  • DOI:
    10.1016/j.freeradbiomed.2015.10.301
  • 发表时间:
    2015-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Andrea Leonardi;Akshaya Chandrasekaran;Thomas J Begley;Juan Andres Melendez
  • 通讯作者:
    Juan Andres Melendez

Thomas J Begley的其他文献

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{{ truncateString('Thomas J Begley', 18)}}的其他基金

Chemical Modifications to Wobble Uridines in tRNA Regulate Responses to Stress
tRNA 中摆动尿苷的化学修饰可调节应激反应
  • 批准号:
    10662193
  • 财政年份:
    2022
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational regulation during cigarette smoking-induced reprogramming of the tRNA epitranscriptome, in vitro and in a mouse smoking model
体外和小鼠吸烟模型中吸烟诱导的 tRNA 表观转录组重编程过程中的翻译调控
  • 批准号:
    10376779
  • 财政年份:
    2020
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational regulation during cigarette smoking-induced reprogramming of the tRNA epitranscriptome, in vitro and in a mouse smoking model
体外和小鼠吸烟模型中吸烟诱导的 tRNA 表观转录组重编程过程中的翻译调控
  • 批准号:
    10186749
  • 财政年份:
    2020
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational regulation during cigarette smoking-induced reprogramming of the tRNA epitranscriptome, in vitro and in a mouse smoking model
体外和小鼠吸烟模型中吸烟诱导的 tRNA 表观转录组重编程过程中的翻译调控
  • 批准号:
    10597055
  • 财政年份:
    2020
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational regulation in exposure biology - Xenobiotic-induced reprograming of tRNA modifications and selective translation of codon-biased response genes in rat and human models
暴露生物学中的翻译调控——在大鼠和人类模型中异种物质诱导的 tRNA 修饰重编程和密码子偏向反应基因的选择性翻译
  • 批准号:
    10693254
  • 财政年份:
    2016
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational regulation in exposure biology: Xenobiotic-induced reprograming oftRNA modifications and selective translation of codon-biased response genes in rat and humanmodels
暴露生物学中的翻译调控:大鼠和人类模型中异生素诱导的 tRNA 修饰重编程和密码子偏向反应基因的选择性翻译
  • 批准号:
    9769034
  • 财政年份:
    2016
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational control of ROS Management
ROS 管理的翻译控制
  • 批准号:
    8911316
  • 财政年份:
    2014
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational control of ROS Management
ROS 管理的翻译控制
  • 批准号:
    9063543
  • 财政年份:
    2014
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational control of ROS Management
ROS 管理的翻译控制
  • 批准号:
    8777772
  • 财政年份:
    2014
  • 资助金额:
    $ 35.77万
  • 项目类别:
Translational control of ROS Management
ROS 管理的翻译控制
  • 批准号:
    9068607
  • 财政年份:
    2014
  • 资助金额:
    $ 35.77万
  • 项目类别:

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