Molecular insight into RNA degradation in health and disease
Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) constitute a conserved family of RNA binding proteins that are important in embryonic development. Isoform 1 expression is tightly linked with neural development and animals lacking IGF2BP1 develop a smaller cortex. At the cell level, IGF2BP1 seems to be important for cell shape, division and migration, while in the brain it regulates the wiring of the nascent neurons to create neural connections. At the molecular level, IGF2BP1 regulates the stability of RNA molecules by recruiting degradation proteins. Accumulating evidence indicates that IGF2BP expression in tumours correlates with cancer dissemination. In hepatocellular carcinoma cells, IGF2BP1 interacts with a specific long non-coding RNA (lncRNA) and regulates its degradation. To shed light into the mechanism of function of IGF2BP1 in cancer, the EU-funded LNCRNATURNOVER (Molecular basis of IGF2BPs-mediated lncRNAs degradation) project proposed to investigate the way it recognises and regulates RNAs. The scientific work focused specifically on the recognition of the RNA targets and the mechanism by which IGF2BP1 binds to the multi-protein complex required for degradation. Scientists developed a novel methodology to assess the contribution of individual domains towards the recognition of cellular targets. The RNA binding capability of individual domains was eliminated through the introduction of mutations and the RNA binding capacity to the cellular RNA was assessed through immunoprecipitation. Results showed that IGF2BP1 uses different combinations of domains to recognise different targets, suggesting that it would be possible to selectively disrupt its function by targeting specific domains with small molecules. Furthermore, researchers observed that IGF2BP1 interacted directly with the multi-protein complex mediating RNA degradation. Taken together, the findings of the study indicate that IGF2BP1 is a finely tuned regulator of specific gene expression programmes. Apart from fundamental knowledge, these results might have clinical implications considering the elevated levels of IGF2BP1 encountered in cancer.
Keywords
Cancer, IGF2BP1, degradation protein, lncRNA, LNCRNATURNOVER
