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EURECA Report Summary

Project ID: 339953
Funded under: FP7-IDEAS-ERC
Country: Denmark

Mid-Term Report Summary - EURECA (Eukaryotic Regulated RNA Catabolism)

A ground-breaking discovery of the past decade has been that up to ~75% 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 is to establish cutting-edge research to characterize mammalian nuclear RNA turnover; its factor utility, substrate specificity and regulatory capacity. In doing so, we will delineate the cellular sorting mechanism 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. The aim is now to pin-point such check-points and describe 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 can now exploit this knowledge to, in a rational way, go hunt for yet additional such co-factors.
Finally, nuclear RNA turnover might also be regulated so to drive cellular differentiation processes. In an on-going approach, we have shown that expression of certain mouse ES cell differentiation markers depend on functional RNA exosome co-factor complexes. Efforts are now focused on delineating the basis for this phenotype, including effects on transcription and/or RNA metabolism.

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