Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes

被引:62
作者
Chan, Clement T. Y. [1 ]
Deng, Wenjun [1 ]
Li, Fugen [2 ]
DeMott, Michael S. [1 ]
Babu, I. Ramesh [1 ]
Begley, Thomas J. [4 ]
Dedon, Peter C. [1 ,3 ]
机构
[1] MIT, Dept Biol Engn, Cambridge, MA 02139 USA
[2] MIT, BioMicro Ctr, Cambridge, MA 02139 USA
[3] MIT, Ctr Environm Hlth Sci, Cambridge, MA 02139 USA
[4] SUNY Albany, Coll Nanoscale Sci, Albany, NY 12203 USA
基金
美国国家科学基金会; 新加坡国家研究基金会;
关键词
BINDING PROTEIN ABP140; BASE EXCISION-REPAIR; ALKYLATING-AGENTS; MASS-SPECTROMETRY; STRESS-RESPONSE; DNA; DATABASE; DAMAGE; METHYLTRANSFERASE; TRANSLATION;
D O I
10.1021/acs.chemrestox.5b00004
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Cells respond to stress by controlling gene expression at several levels, with little-known about the role of translation. Here, We demonstrate a coordinated translational stress response System involving stress-specific reprogramming of tRNA wobble;modifications that leads to selective translation of codon-biased mRNAs representing different classes of critical. response proteins. In budding yeast exposed to four oxidants and five alkylating agents, tRNA modification. patterns accurately distinguished among chemically similar stressors, with 14 modified ribonucleosides forming the basis for a data driven model that predicts toxicant chemistry with >80% sensitivity and specificity. tRNA Modification subpatterns also distinguish S(N)1 from S(N)2 alkylating agents, with S(N)2-induced increases in m(3)C in tRNA mechanistically linked to selective translation of threonine rich membrane proteins from genes enriched with ACC and ACT degenerate codons for threonine. These results establish tRNA modifications as predictive biomarkers of exposure and illustrate a novel regulatory mechanism for translational control of cell stress response.
引用
收藏
页码:978 / 988
页数:11
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