Research Topic: nonsense-mediated mRNA decay

To defend against genetic nonsense mutations, our cells have evolved an mRNA surveillance pathway--nonsense-mediated mRNA decay (NMD)--to selectively degrade mRNAs containing premature stop codons. NMD is also part of the posttranscriptional quality control mechanisms to eliminate errors of transcription or mRNA processing and ensure fidelity of gene expression. What is interesting is that this regulatory pathway in conjunction with alternative splicing is harnessed by our cells to actively fine-tune gene expression level. Such regulation is often called alternative splicing-induced NMD (AS-NMD) or regulated unproductive splicing and translation (RUST).

AS-NMD allows a splicing choice to act as an on/off switch for a final gene product. This is rather different from the commonly perceived outcomes of alternative splicing, i.e. modifying protein structures and activity. For example many splicing regulators maintain homeostatic expression by the AS-NMD mechanism. These splicing factors auto-regulate or cross-regulate their own splicing to produce natural NMD sensitive isoforms. Any increase in their proteins leads to more NMD mRNA isoforms and less productive isoforms. Theoretically for genes that do not regulate their own splicing, AS-NMD can be an effective strategy to modulate overall abundance of their mRNA and protein. However, it is still unclear how widely AS-NMD is employed to control gene expression.

We have found an important AS-NMD target in brain. AS-NMD control of Psd-95 enforces brain specific expression of its protein and regulates its developmental induction for synapse formation. A recent study has found additional AS-NMD targets, Sap102 and Scn9a5. The regulation of two of the five DLG family proteins (Psd95 and Sap102) by AS-NMD suggests that there might be common features of the AS-NMD genes (e.g. synapse-related) that use splicing as an on/off switch for expression, which we are investigating carefully.