Figure 1.

Pathways involved in cell cycle arrest. Established means to identify senescent cells are indicated in red. Ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases play a central role in DNA damage detection and response. Both proteins rapidly phosphorylase histone 2AX. Furthermore, ATM and ATR can both lead to the phosphorylation of the tumor suppressor p53(pSer15) upon DNA damage. Furthermore, ATM phosphorylates the checkpoint kinases Chk1 and Chk2. Chk2 directly phosphorylates p53 at pSer20, leading to the expression of the CKI p21. Phosphorylation of p21 inhibits CDK, leading to the hypophosphorylation of retinoblastoma tumor suppressor (Rb). This enables Rb to bind to E2F, inhibiting cell cycle progression. Likewise, p53 activity can be increased by p38 MAPK activity, induced by ROS, or by binding of p14^ARF to murine double minute 2 (MDM2) preventing degradation of p53 (Elledge and Zhou, 2000; Hirao et al., 2002; Fischer et al., 2016). In addition to p53, the accumulation of the tumor suppressor p16^Ink4a also leads to cell cycle arrest via the inhibition of CDK4/CDK6 and subsequent hypophosphorylation of Rb (Moonen et al., 2018). Abbreviations: BrdU, bromodeoxyuridine.