Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response
Volume 11, Issue 19
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October 1, 2012
Pages 3656 - 3665http://dx.doi.org/10.4161/cc.21919
: DNA damage response, Trm9, cell cycle, codon usage, tRNA, translation
Authors: Ashish Patil, Madhu Dyavaiah, Fraulin Joseph, John P. Rooney, Clement T.Y. Chan, Peter C. Dedon and Thomas J. Begley View affiliations
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.
Received: August 17, 2012; Accepted: August 21, 2012; Published Online: August 30, 2012
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