The molecular mechanism of SNORD116 action (year 2)
Funding Summary
Lay Abstract
SNORD116 is a C/D box small nucleolar RNA that is critical for the etiology of PWS, as microdeletions encompassing only SNORD116 cause a PWS-like phenotype. The molecular functions of SNORD116 have been elusive, preventing therapy design. We showed that SNORD116 is not a typical snoRNA, as it associates with different proteins and has a different cellular localization than 'normal C/D box snoRNAs'. We found that SNORD116's main function is to regulate the stability of mRNAs, generally decresing the stability through direct binding to control regions.
Most of SNORD116's targets are genes that are rapidly induced after neuronal activation and SNORD116's physiologial function could be to accelerate the degradation of these RNAs. Thus SNORD116 ensures that after stimulation mRNAs are rapidly degraded, which generates narrow 'spikes' of increased/decreased mRNA concentration that are necessary for circadian rhythm (day and night cycles) and pulsed hormone release.
We will measure the half-life (i.e. stability) of all mRNAs in PWS and control cells and determine how SNORD116 binds to these mRNAs, which will allow us to test small molecules for their ability to replace SNORD116.
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