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.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR 97%
- Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence 95%
- Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence 95%
Similar papers in this journal
- Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease 91%
- ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells 91%
- Reporter-based screening identifies RAS-RAF stabilizing mutations as drivers of resistance to broad-spectrum RAS inhibition in colorectal cancer 90%
Similar papers in this journal
- A non-canonical Hippo pathway represses the expression of deltaNp63 91%
- The Conserved CNOT1 Interaction Motif of Tristetraprolin Regulates ARE-mRNA Decay Independently of the p38 MAPK-MK2 Kinase Pathway 90%
- Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice 90%
Similar papers in this journal
- Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes 95%
- Hypoxia increases the methylated histones to prevent histone clipping and redistribution of heterochromatin during Raf-induced senescence 94%
- TERRA increases at short telomeres in yeast survivors and regulates survivor associated senescence (SAS) 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.