Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence

The telomere-capping complex (shelterin) protects functional telomeres from initiating unwanted DNA damage response. Uncapped telomeres at the end of cellular replicative lifespan lose this protective mechanism and trigger DNA damage signaling to activate p53 and thereby induce replicative senescence. Here we identify a signaling pathway involving p53, Siah-1, a p53-inducible E3 ubiquitin ligase, and TRF2, a component of the shelterin complex. Endogenous Siah-1 and TRF2 were up- and down-regulated, respectively, at replicative senescence with activated p53. A series of experimental manipulations of p53 showed that p53 induced Siah-1 and repressed TRF2 protein levels. The p53-dependent ubiquitination and proteasomal degradation of TRF2 were attributed to the E3 ligase activity of Siah-1. Siah-1 knockdown stabilized TRF2 and delayed the onset of cellular replicative senescence, suggesting the role of Siah-1 and TRF2 in p53-regulated senescence. This study reveals that p53, a downstream effector of the telomere-initiated damage signaling, also functions upstream of the shelterin complex