Regulation of pre-mRNA confinement in the nucleus during aging and stress response
Description: Nuclear envelope dysmorphia, including clustering and reorganization of the nuclear pore complexes (NPCs), is a universal hallmark of aging in eukaryotes. For example, in the Hutchinson-Gilford progeria syndrome, progerin, a natural variant of Lamin A, is prematurely expressed and causes nuclear dysmorphia, NPC clustering, and the dissociation of the nucleoporin Nup153 and the nuclear basket from NPCs. Likewise, we have reported that the nuclei of yeast cells become distinctly enlarged during replicative aging and that aged cells remodel NPCs by shedding their nuclear basket. However, how nuclear envelope reorganization affects cell physiology and viability is still mysterious. Over the last two years, we have accumulated molecular and functional evidence that NPC remodeling in old yeast cells impairs the confinement of unspliced pre-mRNAs into the nucleus. Pre-mRNA leakage represses the expression of many intron-containing genes (ICGs), while curiously stimulating the expression of other ICGs. This expression modulation is intron-dependent. Moreover, we at least one aging phenotype, chromosome mis-segregation, relied on intron-dependent gene regulation. Based on our observations and available data, we suggest that yeast have undergone positive evolutionary selection to retain their few extant introns because they collectively function in an adaptive pathway. This pathway, which we have termed INSTeAD (for INtron-dependent STress ADaptation), reallocates spliceosome capacity in response to stress. Thereby, it stimulates the expression of ICGs involved in stress adaptation at the expense of those promoting growth. The overall goal of this proposal is to characterize the mechanisms underlying the release of pre-mRNAs from the nucleus in response to stress and to dissect its effects on gene expression, the stress response, adaptation to adverse conditions, and aging.Specifically, we will focus on the following four aims:Aim 1: We will characterize and model the effects of introns, splicing, pre-mRNA leakage, and degradation on ICG expression in exponential growth and in response to stress and age.Aim 2: We will identify molecular factors and discern how cells facilitate pre-mRNA leakage from the nucleus during stress and aging. Here, we will use a candidate approach alongside a more comprehensive and unbiased approach.Taken together, aims 1 and 2 will allow us to define the mechanisms and output of INSTeAD precisely.Aim 3: We will study how INSteAD controls the evolvability of cells facing adverse conditions, using our newly discovered process of chromosome drive.Aim 4: Using the information collected in aims 1-3, we will define the roles of INSTeAD in aging.These studies will shed light on the selective forces that drive intron retention in many eukaryotes, how cells turn mRNA quality control into a powerful stress sensor and orchestrator of gene expression, and how the nuclear envelope contributes to aging. These studies will also tackle the highly debated question of whether evolvability can be a selected trait.
Amount: CHF 960,000
Funding type: research
Funder scheme: Project funding
Start date: 2023-06-01
End date: 2027-05-31
Investigator: Barral, Yves
Institution: ETH Zurich – ETHZ
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 215447
OpenAlex ID: G8246769486