Rewired mRNA homeostasis enforces cell-size associated senescence

Cellular senescence refers to a permanent state of cell cycle exit and plays a key role in blocking the proliferation of compromised cells. Despite diverse drivers, senescent cells often share common features, one of which is their increased size. Though previously viewed as a passive outcome of cell growth during senescence, recent work shows that excess cell size can actively promote senescence via the p53-p21 pathway, making it both a consequence and a cause of cell cycle arrest. How cells sense their own size and communicate this information to the cell cycle control apparatus remains unresolved. Using genome-wide proximity mapping, we show that excess cell size globally redistributes chromatin between nuclear speckles and the nuclear lamina. These changes correspond with altered gene expression profiles, including the de-repression of typically silenced lamina-associated genes, some of which are involved in the senescence-associated secretory phenotype (SASP). Consistent with altered nuclear speckle function, we find that excess cell size perturbs normal splice isoform usage. In particular, MDM4, a negative regulator of p53 signaling, is differentially spliced when cells become enlarged to yield a non-functional variant, MDM4-S. Re-introducing correctly spliced MDM4 transcripts restores G1 cell cycle progression, thereby reverting senescent phenotypes in enlarged cells. Together, these data indicate that excess cell size is sensed via changes in mRNA homeostasis associated with a reorganized genome, driving both the secretory phenotype and permanent cell cycle exit that are characteristic of cellular senescence.