Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype

Thoms, H. C.; Brant, T.; Duckett, K.; Yang, Y.; Dong, J.; Wang, H.; Derby, F.; Akeke, T.; Mann, D.; Millar, F. R.; Von Kriegsheim, A.; Acosta, J. C.; Oakley, F.; Stark, L. A.

doi:10.1101/2023.12.05.570133

bioRxiv · 10.1101/2023.12.05.570133

Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype

Thoms, H. C.·Brant, T.·Duckett, K.·Yang, Y.·Dong, J.·Wang, H.·Derby, F.·Akeke, T.·Mann, D.·Millar, F. R.·Von Kriegsheim, A.·Acosta, J. C.·Oakley, F.·Stark, L. A.

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Abstract

Two key characteristics of senescent cells are nucleolar fusion and secretion of a plethora of pro-inflammatory cytokines called the senescence-associated secretory phenotype (SASP). The SASP is dependent on NF-{kappa}B but the initial trigger, and links with nucleoli, are unclear. Using multiple in vitro and in vivo models, we show that an early response to oncogene- and therapy-induced senescence (OIS and TIS) is nuclear/nucleolar accumulation of the PolI complex component, TIF-IA. This accumulation is essential for nucleolar fusion, the SASP and senescence, independent of rDNA transcription. We show that in steady state, TIF-IA is targeted for autophagic degradation by the p62 cargo receptor and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts the p62-TIF-IA interaction. In mice, TIF-IA accumulates in colonic mucosa with age, which is further enhanced in the nfkb1-/- model of accelerated ageing. Together, these results reveal a p62-TIF-IA nucleolar stress axis that regulates the SASP and senescence, and that warrants further investigation as an anti-ageing target.

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Thoms, H. C., Brant, T., Duckett, K., Yang, Y., Dong, J., Wang, H., Derby, F., Akeke, T., Mann, D., Millar, F. R., Von Kriegsheim, A., Acosta, J. C., Oakley, F., Stark, L. A.. 2023-12-06. Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype. https://doi.org/10.1101/2023.12.05.570133

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