TPR is required for cytoplasmic chromatin fragment formation during senescence

During oncogene-induced senescence there are striking changes in the organisation of
heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory
gene expression programme – the senescence associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin
re-organisation and the SASP has been unclear. Here we show that TPR, a protein of the
nuclear pore complex basket required for heterochromatin re-organisation during
senescence, is also required for the very early activation of NF-κB signalling during the
stress-response phase of oncogene-induced senescence. This is prior to activation of the
SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required
for the activation of innate immune signalling at these early stages of senescence and we
link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments
thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for
cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear
periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.