The findings from this study provide valuable insights into the mechanisms underlying the PML-nucleolar response to topological stress and rDNA damage, offering potential opportunities for the development of novel therapeutic strategies. Targeting the formation of PML-nucleolar compartments (PNAs) could be a promising approach to modulate cellular senescence, particularly in cancer cells where senescence induction can inhibit tumor growth. By understanding the signaling pathways and molecular interactions involved in PNAs formation, researchers may identify druggable targets that can disrupt or prevent the assembly of PNAs in response to topological stress and rDNA damage. Furthermore, targeting specific components of the PML-nucleolar response, such as ATM/ATR kinases or homologous recombination factors, could offer new avenues for therapeutic intervention in diseases associated with nucleolar stress and genomic instability. Leveraging the insights from this study could lead to the development of targeted therapies aimed at modulating the PML-nucleolar response for clinical applications in cancer treatment and age-related disorders.