Establishing a reporter assay to identify small molecule NMD inhibitors and new NMD factors

The role of nonsense-mediated mRNA decay (NMD) on the manifestation of human disease has been a subject of intense research for decades. The limiting step however for uncovering the physiological role of the surveillance pathway and its implications in genetic diseases has been the fact that the mechanistic aspects of NMD have yet to be fully elucidated. In this context, we have been working towards identifying novel NMD factors and potential low molecular weight compounds that act as NMD inhibitors. In a collaboration with Novartis we tested for NMD inhibition two leader compounds previously identified to promote ribosome readthrough and found them to significantly reduce the mRNA levels of the tested NMD reporters. In parallel, an improved version of our fluorescence-based NMD reporter system is currently being developed, which will be used for genome-wide siRNA screens to identify new NMD factors and for small molecule screens to identify new NMD inhibitors.