Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response
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...
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| Format: | Article |
| Language: | en_US |
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Taylor & Francis
2014
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| Online Access: | http://hdl.handle.net/1721.1/91232 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7940-3459 |
| _version_ | 1811094359835148288 |
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| author | Patil, Ashish Dyavaiah, Madhu Joseph, Fraulin Rooney, John P. Chan, Tsz Yan Clement Dedon, Peter C. Begley, Thomas J. |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Patil, Ashish Dyavaiah, Madhu Joseph, Fraulin Rooney, John P. Chan, Tsz Yan Clement Dedon, Peter C. Begley, Thomas J. |
| author_sort | Patil, Ashish |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:58:48Z |
| format | Article |
| id | mit-1721.1/91232 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:58:48Z |
| publishDate | 2014 |
| publisher | Taylor & Francis |
| record_format | dspace |
| spelling | mit-1721.1/912322022-09-29T17:24:53Z Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response Patil, Ashish Dyavaiah, Madhu Joseph, Fraulin Rooney, John P. Chan, Tsz Yan Clement Dedon, Peter C. Begley, Thomas J. Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Dedon, Peter C. Chan, Tsz Yan Clement Dedon, Peter C. 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. National Institute of Environmental Health Sciences (R01 ES015037) National Institute of Environmental Health Sciences (R01 ES017010) National Institute of Environmental Health Sciences (P30 ES002109) Massachusetts Institute of Technology (Westaway Fund) Singapore-MIT Alliance for Research and Technology 2014-10-29T20:04:36Z 2014-10-29T20:04:36Z 2014-10 2012-08 Article http://purl.org/eprint/type/JournalArticle 1538-4101 1551-4005 http://hdl.handle.net/1721.1/91232 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. https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7940-3459 en_US http://dx.doi.org/10.4161/cc.21919 Cell Cycle Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Taylor & Francis Prof. Dedon via Howard Sliver |
| spellingShingle | Patil, Ashish Dyavaiah, Madhu Joseph, Fraulin Rooney, John P. Chan, Tsz Yan Clement Dedon, Peter C. Begley, Thomas J. Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title | Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title_full | Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title_fullStr | Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title_full_unstemmed | Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title_short | Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response |
| title_sort | increased trna modification and gene specific codon usage regulate cell cycle progression during the dna damage response |
| url | http://hdl.handle.net/1721.1/91232 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7940-3459 |
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