Figure 8 | Scientific Reports

Figure 8

From: Whole Chromosome Instability induces senescence and promotes SASP

Figure 8

Proposed model for mechanisms of W-CIN induced senescence and SASP.

Several mechanisms can explain senescence induction through W-CIN, involving the TP53/CDKN1A, CDKN2A/RB1 or ARF pathways. (a) W-CIN generates polyploid and/or multinucleated cells through cytokinesis failure and aneuploid cells through mis-segregation of chromosomes. Because polyploid cells are unstable, they can evolve to an unbalanced aneuploid state. (b) Cytokinesis failure leads to extra centrosomes and reduced RhoA activity, which in turn results in indirect stabilization of TP53 via LATS2-inhibition of MDM2 function. (c) Chromatin trapped in the cleavage furrow can activate ATM and thus, TP53. (d) Polyploid and aneuploid cells generate elevated ROS levels that can activate the CDKN2A/RB1 pathway. Alternatively, ATM activation directly by ROS or via oxidative DNA/RNA damage can also turn on TP53. (e) Chromosome mis-segregation potentially produces micronuclei and replication stress, both of which activate DDR, ATM and TP53. (f) Aneuploidy-induced protein imbalances caused by gain or loss of specific chromosomes can have 2 consequences: disruption of cellular redox homeostasis leading to ROS overproduction, and mitochondrial dysfunction due to uneven production of mitochondrial proteins. In the latter case, AMPK activation result in TP53-dependent senescence. (g) Multinucleation and aneuploidy can up-regulate ARF through DNA damage generation or other pathways, triggering senescence by TP53 activation or trough other TP53 independent mechanisms. (h) W-CIN induced SASP comprise factors signature of DNA damage (yellow box), mitochondrial dysfunction (pink box) and by also a novel growth factor CLEC11A (purple box). Factors such as CCL2 and IL1B induce paracrine bystander senescence, potentially spreading the senescence phenotype to normal diploid cells. Nevertheless, all the above-mentioned mechanisms are not mutually exclusive.

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