TOP2A Maintains Heterochromatin Stability by Sustaining LMNB1 Expression to Counteract Senescence.

Abstract

Chromatin stability and nuclear architectural integrity constitute the primary defense against cellular senescence. Their collapse precipitates genomic disarray, epigenetic misregulation, and functional decline in stem cells. Although TOP2A is conventionally known for resolving DNA topological stress, its role in aging remains largely unexplored. Here, we found that TOP2A expression progressively decreased in senescent mesenchymal stem cells (MSCs), and its depletion initiated a catastrophic nuclear remodeling process characterized by the loss of Lamin B1, heterochromatin erosion, and senescence-associated phenotypes. Mechanistically, TOP2A directly regulated the expression of Lamin B1 to maintain nuclear architecture. TOP2A depletion set off a domino effect involving nuclear membrane rupture, loss of heterochromatin-associated factors (H3K9me3, KAP1, and LAP2), deterioration of cellular functions and acceleration of senescence. Notably, overexpression of TOP2A restored Lamin B1 levels, mitigated nuclear protein loss, preserved nuclear integrity, and counteracted cellular senescence. The in vivo relevance of these findings was further underscored by TOP2A inhibitor-induced brain aging in murine models. Our study establishes TOP2A as a novel modulator of cellular senescence, which stabilizes heterochromatin and nuclear structure, and provides new perspectives for targeting chromatin-based mechanisms in aging.