Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response
Name
Patil et al Final Manuscript 2012 8-7.pdf
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entire manuscript
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Author(s)
Patil, Ashish
Dyavaiah, Madhu
Joseph, Fraulin
Rooney, John P.
Chan, Tsz Yan Clement
Dedon, Peter C.
Begley, Thomas J.
Date Issued
October 2014
Journal
Cell Cycle
Publisher
Taylor & Francis
Citation
Patil, Ashish, Madhu Dyavaiah, Fraulin Joseph, John P. Rooney, Clement T.Y. Chan, Peter C. Dedon, and Thomas J. Begley. “Increased tRNA Modification and Gene-Specific Codon Usage Regulate Cell Cycle Progression During the DNA Damage Response.” Cell Cycle 11, no. 19 (October 1, 2012): 3656–3665.
Version
Author's final manuscript
Abstract
S-phase and DNA damage promote increased ribonucleotide reductase (RNR) activity. Translation of RNR1 has been linked to the wobble uridine modifying enzyme tRNA methyltransferase 9 (Trm9). We predicted that changes in tRNA modification would translationally regulate RNR1 after DNA damage to promote cell cycle progression. In support, we demonstrate that the Trm9-dependent tRNA modification 5-methoxycarbonylmethyluridine (mcm⁵U) is increased in hydroxyurea (HU)-induced S-phase cells, relative to G₁ and G₂, and that mcm⁵U is one of 16 tRNA modifications whose levels oscillate during the cell cycle. Codon-reporter data matches the mcm⁵U increase to Trm9 and the efficient translation of AGA codons and RNR1. Further, we show that in trm9Δ cells reduced Rnr1 protein levels cause delayed transition into S-phase after damage. Codon re-engineering of RNR1 increased the number of trm9Δ cells that have transitioned into S-phase 1 h after DNA damage and that have increased Rnr1 protein levels, similar to that of wild-type cells expressing native RNR1. Our data supports a model in which codon usage and tRNA modification are regulatory components of the DNA damage response, with both playing vital roles in cell cycle progression.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.4161/cc.21919
