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Eukaryotic Regulated RNA Catabolism

Final Report Summary - EURECA (Eukaryotic Regulated RNA Catabolism)

A ground-breaking discovery of the past decade has been that up to -80-90% of the human genome is transcriptionally active. However, the fates of these diverse RNAs differ substantially as some are rapidly degraded while others remain stable and exercise various functions in the cell. What is the underlying mechanism? The intention of the EURECA proposal has been to establish cutting-edge re search to characterize mammalian nuclear RNA turnover; its factor utility, substrate specificity and regulatory capacity. In doing so, we have delineated aspects of the cellular sorting mechanisms discriminating RNA for productive purposes or for destruction.

Transcript fate decisions are ultimately dictated by the proteins with which the nascent RNA associate. We have employed in vivo cross-linking technology and biochemical approaches to delineate the RNA binding profiles of early associating destructive/productive factors and found that these proteins all bind capped RNAs without strong preferences for individual transcripts. We therefore suggest that RNA fate involves the transient formation of mutually exclusive complexes, occurring at particular check-points during RNA biogenesis. In the project, we have pin-pointed such check- points and described their underlying biological mechanisms.
We have also characterized a new co-factor for the ribonucleolytic RNA exosome, mediating the majority of RNA turnover in mammalian nuclei, called the 'PolyA tail eXosome Targeting (PAXT) connection' and described its substrate preferences. This has revealed a common strategy for exosomal degradation of RNA; different co-factor are employed to target the exosome to its multitude of substrates. We are now exploiting this knowledge to, in a rational way, go hunt for yet additional co- factors of nuclear RNA decay.
Finally, nuclear RNA turnover might also be regulated so to drive cellular differentiation processes. Within the project, we have shown that mis-expression of RNA decay complexes in mouse ES cells seriously disturbs the differentiation process by altering usual developmental transcription programs. This unprecedented link between RNA turnover and transcription machineries will now be characterized and its physiological impact in organism development will be delineated.