title: A quantitative systems approach reveals dynamic control of tRNA modifications during cellular stress.
abstract: Decades of study have revealed more than 100 ribonucleoside structures incorporated as post-transcriptional modifications mainly in tRNA and rRNA, yet the larger functional dynamics of this conserved system are unclear. To this end, we developed a highly precise mass spectrometric method to quantify tRNA modifications in Saccharomyces cerevisiae. Our approach revealed several novel biosynthetic pathways for RNA modifications and led to the discovery of signature changes in the spectrum of tRNA modifications in the damage response to mechanistically different toxicants. This is illustrated with the RNA modifications Cm, m(5)C, and m(2) (2)G, which increase following hydrogen peroxide exposure but decrease or are unaffected by exposure to methylmethane sulfonate, arsenite, and hypochlorite. Cytotoxic hypersensitivity to hydrogen peroxide is conferred by loss of enzymes catalyzing the formation of Cm, m(5)C, and m(2) (2)G, which demonstrates that tRNA modifications are critical features of the cellular stress response. The results of our study support a general model of dynamic control of tRNA modifications in cellular response pathways and add to the growing repertoire of mechanisms controlling translational responses in cells.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Clement T Y
authors.initials: CT
authors.lastname: Chan
authors.forename: Madhu
authors.initials: M
authors.lastname: Dyavaiah
authors.forename: Michael S
authors.initials: MS
authors.lastname: DeMott
authors.forename: Koli
authors.initials: K
authors.lastname: Taghizadeh
authors.forename: Peter C
authors.initials: PC
authors.lastname: Dedon
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Begley
mesh_terms: D012323:RNA Processing, Post-Transcriptional; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D012343:RNA, Transfer