Abstract
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.
Highlights
Three-dimensional (3D) genome organization is governed by a combination of polymer biophysics and biochemical interactions, including local chromatin compaction, longrange chromatin interactions, and interactions with nuclear structures
Another situation in which there is a dramatic reorganization of heterochromatin is in oncogene-induced senescence (OIS)—a cell cycle arrest program triggered by oncogenic signaling
We demonstrated the functional consequences of heterochromatin reorganization in OIS for the programmed activation of inflammatory cytokine gene expression: the senescence-associated secretory phenotype (SASP)
Summary
Nuclear pore density controls heterochromatin reorganization during senescence Charlene Boumendil, Priya Hari, Karl C.F. Altered NL composition in the photoreceptors of nocturnal mammals leads to the loss of heterochromatin from the nuclear periphery and its accumulation at the center of the nucleus (Solovei et al 2013) Another situation in which there is a dramatic reorganization of heterochromatin is in oncogene-induced senescence (OIS)—a cell cycle arrest program triggered by oncogenic signaling. We hypothesized that the NPC could contribute to global chromatin organization and that, heterochromatin organization could result from a balance of forces attracting heterochromatin to the NL and forces repelling it away from the NPC (Fig. 1B) In support of this hypothesis, we show here that nuclear pore density increases during OIS and that this increase is necessary for heterochromatin reorganization into SAHFs. We identified TPR as a key player in this reorganization. GENES & DEVELOPMENT 33:144–149 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/19; www.genesdev.org
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