DNA circles promote yeast ageing in part through stimulating the reorganization of Nuclear Pore Complexes
A recent "eLife" paper by the Barral (IBC) and Charvin (IGBMC, Strasbourg) groups demonstrates that age remodels yeast Nuclear Pore Complexes (NPCs), resulting in changes of NPC-associated transport machinery, and dissect the role of extrachromosomal DNA and the SAGA-complex in these changes.
Changes in the composition of the Nuclear Pore Complex (NPCs), the gateway between the nucleus and cytoplasm of eukaryotic cells, is a hallmark of ageing from yeast to mammals. However, the mechanisms of these changes were not known. Particularly, it was not known whether they were due to NPC damage or resulted from regulatory events.
In budding yeast, chromosomal excision and accumulation of extrachromosomal DNA circles are a major driver of ageing. Researchers in the Barral lab discovered that DNA circles bind and actively modulate NPC organization through the acetyltransferase complex SAGA. Acetylation of the NPCs by SAGA dissociates their nuclear basket and cytoplasmic complex. As a consequence, these NPCs lose key effectors involved in mRNA quality control and export from the nucleus.
Remarkably, these remodeled NPCs were not recognized as defective by the quality control machinery of the cell. They did not cause leakage of proteins out of the nucleus either, unlike what would be expected from defective NPCs. Furthermore, in young cells, the same acetylation events on NPCs play a physiologically important role in the regulation of nucleo-cytoplasmic exchange. Thus, this study suggests that the NPCs of old cells are not damaged but in a specialized state.
It is currently unclear how extrachromosomal DNA circles contribute to ageing and pathology. This work demonstrates that they impact the gateway between nucleus and cytoplasm. How this extensive remodeling of NPCs and its apparent effect on mRNA export affects physiology and promotes ageing is the question opened by this study.
Link to the paper in external pageeLife