Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response.

Cell Cycle 2012 Oct 30;11(19):3656-65. Epub 2012 Aug 30.

College of Nanoscale Science and Engineering, University at Albany, State University of New York, Albany, NY, USA.

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 (mcm(5)U) is increased in hydroxyurea (HU)-induced S-phase cells, relative to G(1) and G(2), and that mcm(5)U is one of 16 tRNA modifications whose levels oscillate during the cell cycle. Codon-reporter data matches the mcm(5)U 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.

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http://dx.doi.org/10.4161/cc.21919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478316PMC
October 2012
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(Supplied by CrossRef)
Damage recovery pathways in Saccharomyces cerevisiae revealed by genomic phenotyping and interactome mapping
Begley et al.
Mol Cancer Res 2002
Complete analysis of cellular nucleotides by two-dimensional thin layer chromatography
Bochner et al.
J Biol Chem 1982

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