Research Paper Volume 15, Issue 10 pp 4012—4034

Figure 6. Mechanisms proposed in this study. p53/p21-p16/RB-E2F-DREAM repressor complex controls senescence. p16^INK4A and p53 are two master regulators of cellular senescence. Cell stress or DNA damage signals lead to activation p53 and transcriptional upregulation of the CDK inhibitor p21/CDKN1A, which in-turn hypophosphorylates RB. Activation of p16 ^INK4A controls phosphorylation of RB by binding to CDK4/6 and inhibiting the action of cyclin D. The active form of RB interacts with E2F to restrict transcription of genes that control cell cycle transition. RB-E2F and DREAM complex appear to cooperate to repress many genes that are required for G1/2 to G2/M transitions, potentially leading to impaired proliferation, defective DNA damage repair, altered chromatin, and establishment of senescence. (Created with BioRender.com).