5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion
Abstract Nonsense‐mediated RNA decay (NMD) is an RNA‐based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one‐third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that i...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2014-10-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201404461 |
| _version_ | 1827015240290664448 |
|---|---|
| author | Madhuri Bhuvanagiri Joe Lewis Kerstin Putzker Jonas P Becker Stefan Leicht Jeroen Krijgsveld Richa Batra Brad Turnwald Bogdan Jovanovic Christian Hauer Jana Sieber Matthias W Hentze Andreas E Kulozik |
| author_facet | Madhuri Bhuvanagiri Joe Lewis Kerstin Putzker Jonas P Becker Stefan Leicht Jeroen Krijgsveld Richa Batra Brad Turnwald Bogdan Jovanovic Christian Hauer Jana Sieber Matthias W Hentze Andreas E Kulozik |
| author_sort | Madhuri Bhuvanagiri |
| collection | DOAJ |
| description | Abstract Nonsense‐mediated RNA decay (NMD) is an RNA‐based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one‐third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5‐azacytidine is an analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5‐azacytidine inhibits NMD in a dose‐dependent fashion specifically upregulating the expression of both PTC‐containing mutant and cellular NMD targets. Moreover, this activity of 5‐azacytidine depends on the induction of MYC expression, thus providing a link between the effect of this drug and one of the key cellular pathways that are known to affect NMD activity. Furthermore, the effective concentration of 5‐azacytidine in cells corresponds to drug levels used in patients, qualifying 5‐azacytidine as a candidate drug that could potentially be repurposed for the treatment of Mendelian and acquired genetic diseases that are caused by PTC mutations. |
| first_indexed | 2024-03-07T16:44:51Z |
| format | Article |
| id | doaj.art-f60c809ba8904c2d9ca28ebfc530c5e8 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:19:19Z |
| publishDate | 2014-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-f60c809ba8904c2d9ca28ebfc530c5e82024-10-28T08:53:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842014-10-016121593160910.15252/emmm.2014044615‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashionMadhuri Bhuvanagiri0Joe Lewis1Kerstin Putzker2Jonas P Becker3Stefan Leicht4Jeroen Krijgsveld5Richa Batra6Brad Turnwald7Bogdan Jovanovic8Christian Hauer9Jana Sieber10Matthias W Hentze11Andreas E Kulozik12Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergEuropean Molecular Biology LaboratoryEuropean Molecular Biology LaboratoryMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergEuropean Molecular Biology LaboratoryEuropean Molecular Biology LaboratoryDepartment of Mathematics and Computer Science, University of Southern DenmarkMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergCentre for Molecular Biology of the University of Heidelberg, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergMolecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of HeidelbergAbstract Nonsense‐mediated RNA decay (NMD) is an RNA‐based quality control mechanism that eliminates transcripts bearing premature translation termination codons (PTC). Approximately, one‐third of all inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5‐azacytidine is an analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5‐azacytidine inhibits NMD in a dose‐dependent fashion specifically upregulating the expression of both PTC‐containing mutant and cellular NMD targets. Moreover, this activity of 5‐azacytidine depends on the induction of MYC expression, thus providing a link between the effect of this drug and one of the key cellular pathways that are known to affect NMD activity. Furthermore, the effective concentration of 5‐azacytidine in cells corresponds to drug levels used in patients, qualifying 5‐azacytidine as a candidate drug that could potentially be repurposed for the treatment of Mendelian and acquired genetic diseases that are caused by PTC mutations.https://doi.org/10.15252/emmm.2014044615‐azacytidineMYCnonsense‐mediated decaypremature termination codons |
| spellingShingle | Madhuri Bhuvanagiri Joe Lewis Kerstin Putzker Jonas P Becker Stefan Leicht Jeroen Krijgsveld Richa Batra Brad Turnwald Bogdan Jovanovic Christian Hauer Jana Sieber Matthias W Hentze Andreas E Kulozik 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion EMBO Molecular Medicine 5‐azacytidine MYC nonsense‐mediated decay premature termination codons |
| title | 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion |
| title_full | 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion |
| title_fullStr | 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion |
| title_full_unstemmed | 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion |
| title_short | 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion |
| title_sort | 5 azacytidine inhibits nonsense mediated decay in a myc dependent fashion |
| topic | 5‐azacytidine MYC nonsense‐mediated decay premature termination codons |
| url | https://doi.org/10.15252/emmm.201404461 |
| work_keys_str_mv | AT madhuribhuvanagiri 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT joelewis 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT kerstinputzker 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT jonaspbecker 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT stefanleicht 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT jeroenkrijgsveld 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT richabatra 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT bradturnwald 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT bogdanjovanovic 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT christianhauer 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT janasieber 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT matthiaswhentze 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion AT andreasekulozik 5azacytidineinhibitsnonsensemediateddecayinamycdependentfashion |