Pre-mRNA leakage out of the nucleus as an ancestral mechanism of aging, stress adaptation and pest control?

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Several seminars are held weekly at the Instituto Gulbenkian de Ciência, an initiative that aims to bring together all researchers around the topics under discussion.

The sessions, with internal researchers or guests, contribute to stimulate the open and extremely collaborative culture of the IGC.

You can read the abstract of this seminar to learn more about it.


Using budding yeast as a model to study the mechanisms of replicative aging, we recently established that remodeling of nuclear pore complexes (NPCs), whereby NPCs become stripped of their nuclear basket, is a key event in aging, also observed in many other organisms.  Interestingly, it is also a common stress-response event.  Here, I will present our most recent progress in the attempt to understand the relevance of NPC remodeling and discuss the possibility that this event may actually coordinate and link many stress response events. I will also demonstrate that it coordinates many, if not all phenotypes of aging.  Indeed, basket-less NPCs acted in a dominant manner to trigger phenotypes as diverse as P-body formation, senescence entry and chromosome loss.  Strikingly, in all these cases stripped NPCs did so by promoting the leakage of pre-mRNAs out of the nucleus.  While this last event caused the down-regulation of most intron containing transcripts, the resulting liberation of spliceosome capacity also enhanced the splicing efficiency of few dedicated transcripts, leading to the up-regulation of their expression.  Aging phenotypes resulted from the combined action of these two effects.  Together, our data identify a selected, intron- and NPC-dependent program for the global regulation of gene expression in response to stress.  Curiously, this program turns into a death pathway with age.  I will discuss the biological relevance and evolutionary consequences of this observation, its probable conservation in metazoans, and the possibility that it offers a unifying model for the emergence and coordination of aging processes. Finally, I will develop the notion that this ancestral pathway may have originally evolved to limit the propagation of intracellular pathogens.


Yves Barral
ETH Zürich, Zürich, Switzerland


Marco Fumasoni

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