Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability

  • Nelson J
  • Moore K
  • Chapin A
  • et al.
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Abstract

The nonsense-mediated mRNA decay (NMD) pathway functions to degrade both abnormal and wild-type mRNAs. NMD is essential for viability in most organisms, but the molecular basis for this requirement is unknown. Here we show that a single, conserved NMD target, the mRNA coding for the stress response factor growth arrest and DNA-damage inducible 45 (GADD45) can account for lethality in Drosophila lacking core NMD genes. Moreover, depletion of Gadd45 in mammalian cells rescues the cell survival defects associated with NMD knockdown. Our findings demonstrate that degradation of Gadd45 mRNA is the essential NMD function and, surprisingly, that the surveillance of abnormal mRNAs by this pathway is not necessarily required for viability.Messenger RNA (mRNA) molecules act as the templates from which proteins are made, and so control the amount of protein in a cell. Having too much of certain proteins can harm cells. Additionally, some mRNAs contain errors, and so can create faulty proteins that may also harm the cell.Cells have therefore developed ways to destroy excess or error-ridden mRNAs to avoid a deadly build up of proteins. One such quality control mechanism is called nonsense-mediated decay (NMD). This mechanism is so important that cells that cannot perform nonsense-mediated decay die, although it is not clear exactly what kills the cells.Now, Nelson et al. have found that fruit flies whose cells are unable to perform nonsense-mediated decay die because a harmful protein called Gadd45 builds up in the cells. In normal cells, nonsense-mediated decay destroys the mRNA that relays the instructions for making Gadd45, which keeps the amount of the Gadd45 protein in the cell low. Further experiments show that removing Gadd45 from cells that lack nonsense-mediated decay saves the flies. Removing Gadd45 from human and mouse cells that are unable to perform nonsense-mediated decay also allows these cells to survive.These findings imply that the only nonsense-mediated decay function needed for cells to live is the destruction of Gadd45 mRNA. This further implies that most faulty and normal mRNAs that are normally destroyed by nonsense-mediated decay do not cause the cells to die when nonsense-mediated decay is lost.Learning that creating faulty proteins when nonsense-mediated decay is lost is not necessarily harmful to cells opens new possibilities to treating numerous genetic diseases. In some diseases, cells can only produce faulty forms of a particular protein. Nonsense-mediated decay normally destroys all of these mutant proteins, but it may sometimes be better to have faulty versions of a protein than to have none of it. Safely getting rid of nonsense-mediated decay by also eliminating Gadd45 from cells may therefore be a treatment strategy worth exploring.

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Nelson, J. O., Moore, K. A., Chapin, A., Hollien, J., & Metzstein, M. M. (2016). Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. ELife, 5. https://doi.org/10.7554/elife.12876

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