During oncogene-induced senescence (OIS), heterochromatin is lost from the nuclear periphery and forms internal senescence-associated heterochromatin foci (SAHFs). We show that an increased nuclear pore density during OIS is responsible for SAHF formation. In particular, the nucleoporin TPR is necessary for both formation and maintenance of SAHFs. Loss of SAHFs does not affect cell cycle arrest but abrogates the senescence-associated secretory phenotype—a program of inflammatory cytokine gene activation. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and demonstrate the importance of heterochromatin organization for a specific gene activation program.

Aberrant NF-κB activity drives many of the hallmarks of cancer and plays a key role in cancer progression. Nucleolar sequestration of NF-κB/RelA is one mechanism that switches off this activity and induces the death of cancer cells. Here we define a novel role for the autophagy receptor, SQSTM1/p62 in transport of nucleoplasmic NF-κB/RelA to nucleoli.Identification of this new trafficking mechanism opens up avenues for the development of a unique class of therapeutic agents that transport RelA and other cancer regulatory proteins to this organelle..

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