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Our genome produces RNA that either gives rise to protein or to independent RNA molecules. However, genomic DNA is hyperactive, and only a fraction of the RNA produced ends up as functional molecules - the rest is degraded.

Which molecular machines detect and remove undesirable RNA so that cells do not drown in their own molecular waste? That is the question, "Exo-Adapt" will address over the next six years.

Brief project description

Regulation and fidelity of gene expression is fundamental to the differentiation and maintenance of all living organisms. A central player here is the ribonucleolytic RNA exosome complex, which is involved in the processing and complete turnover of virtually all transcripts types.

The core complex of the exosome has been comprehensively studied, revealing that it is merely a general RNA degradation machine. Instead, specific recognition of its multitude of substrates is achieved by the association of the exosome with so-called protein adaptor complexes.

Although some of these have been identified, we do not understand how they recognize and discriminate their substrates, how they interact with the exosome and how these interactions are regulated to achieve adequate RNA turnover at steady state or in dynamic cellular settings. Furthermore, knowledge of the full spectrum of exosome adaptor complexes and their compositions is lacking. Finally, given the fundamental position of the exosome in cellular RNA biology, it is not surprising that the system is subject to intense targeting by cellular pathogens.

The present Exo-Adapt initiative aims at understanding the human exosome adaptors both in depth and in breadth. Capitalizing on the standing of Exo-Adapt participants as world-leading experts in RNA exosome biology, it is our vision to:

  • characterize biochemically, structurally and functionally how adaptor complexes interact with the mammalian exosome to ‘feed’ it with specific RNA substrates
  • identify new mammalian exosome adaptor complexes and describe their protein constituents and protein-protein interactions at the atomic level
  • place our findings in the context of exosome-pathogen interactions. In doing so, we will educate MSc, PhD and postdoctoral students to become new leaders of academic or industrial activities, by collaborating across the fields of structural, functional and computational biology.

Figure: The human nuclear exosome and its network of cofactors

The human nuclear exosome is comprised of nine catalytically inert subunits (EXO9), associating with distinct ribonucleases (RRP44, RRP6) and co-factors (MPP6 and RRP47) in the nucleoplasm (EXO13) and without RRP44 in the nucleolus (EXO12).

Exo-Adapt focuses on nuclear exosome adaptor complexes hTRAMP (MTR4, ZCCHC7, hTRF4-2), NEXT (MTR4, ZCCHC8, RBM7) and PAXT (MTR4, ZFC3H1, PABPN1, and additional components) previous characterized in Torben Heick Jensen's laboratory as well as yet-to-be-discovered adaptor complexes (question marks). Established connections to the cap binding complex (CBC) will also be investigated.

Outcome and impact

Rationalizing how cells deal with a colossal RNA output from their genomes represents a major challenge in contemporary biology and unfolding the structure, function and regulation of the protein complexes involved is an ambitious step towards this goal. Taken together with the central position of the RNA exosome in the cell nucleus and its direct targeting by pathogens, the suggested research promises to yield ground-breaking new insight impacting basic molecular biology, while also evoking new potential strategies for biomedical utility.

Of general interest beyond exosome biology, we anticipate to reveal details about the so far elusive mechanisms of Zn-finger protein function and how PTMs modify/regulate these proteins.

We will also refine integrated strategies for interaction topology mapping with structural determination of multi-protein complexes, which will be generally applicable.