Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival
tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridi...
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| Format: | Article |
| Language: | en_US |
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American Society for Microbiology
2011
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| Online Access: | http://hdl.handle.net/1721.1/66893 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7808-4281 https://orcid.org/0000-0001-7940-3459 https://orcid.org/0000-0002-7112-1454 |
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| author | Fu, Dragony Brophy, Jennifer Ann Atmore, Kyle Aaquil Begley, Ulrike Begley, Thomas J. Paules, Richard S. Chan, Clement T. Y. Dedon, Peter C Samson, Leona D |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Fu, Dragony Brophy, Jennifer Ann Atmore, Kyle Aaquil Begley, Ulrike Begley, Thomas J. Paules, Richard S. Chan, Clement T. Y. Dedon, Peter C Samson, Leona D |
| author_sort | Fu, Dragony |
| collection | MIT |
| description | tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm[superscript 5]U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm5U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm[superscript 5]U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification. |
| first_indexed | 2024-09-23T14:23:46Z |
| format | Article |
| id | mit-1721.1/66893 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:23:46Z |
| publishDate | 2011 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | mit-1721.1/668932022-09-29T09:12:34Z Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival Fu, Dragony Brophy, Jennifer Ann Atmore, Kyle Aaquil Begley, Ulrike Begley, Thomas J. Paules, Richard S. Chan, Clement T. Y. Dedon, Peter C Samson, Leona D Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Samson, Leona D. Fu, Dragony Brophy, Jennifer Ann Chan, Tsz Yan Clement Atmore, Kyle Aaquil Dedon, Peter C. Samson, Leona D. tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm[superscript 5]U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm5U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm[superscript 5]U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification. United States. National Institutes of Health (grant CA055042) United States. National Institutes of Health (grant ES002109) United States. National Institutes of Health (grant ES01701) National Institutes of Health (U.S.). Intramural Research Program Westaway Research Fund National Center for Research Resources (U.S.) (grant S10-RR023783) 2011-11-02T17:55:21Z 2011-11-02T17:55:21Z 2010-03 2010-01 Article http://purl.org/eprint/type/JournalArticle 0270-7306 1098-5549 http://hdl.handle.net/1721.1/66893 Fu, D. et al. “Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival.” Molecular and Cellular Biology 30 (2010): 2449-2459. Web. 2 Nov. 2011. © 2010 American Society for Microbiology https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7808-4281 https://orcid.org/0000-0001-7940-3459 https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.1128/mcb.01604-09 Molecular and Cellular Biology Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Society for Microbiology PubMed Central |
| spellingShingle | Fu, Dragony Brophy, Jennifer Ann Atmore, Kyle Aaquil Begley, Ulrike Begley, Thomas J. Paules, Richard S. Chan, Clement T. Y. Dedon, Peter C Samson, Leona D Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title | Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title_full | Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title_fullStr | Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title_full_unstemmed | Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title_short | Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival |
| title_sort | human alkb homolog abh8 is a trna methyltransferase required for wobble uridine modification and dna damage survival |
| url | http://hdl.handle.net/1721.1/66893 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0001-7808-4281 https://orcid.org/0000-0001-7940-3459 https://orcid.org/0000-0002-7112-1454 |
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