HuR orchestrates the Stabilization of TINF2 Expression and Telomere Shortening

Shortened telomeres and stabilization of ARF tumor suppressors are most characteristic properties during a replicative senescence. In primary cells, telomeres are gradually shortened via the incomplete DNA replication. At the same time, ARF tumor suppressors are controlled by post-transcriptional regulatory processes, notably mRNA turnover and translation. Many such processes involve in RNA binding proteins (RBPs) that selectively control the expression of subsets of genes. HuR (human antigen R), which is a member of the elav/hu family, facilitates senescent process through stabilizing mRNA of the ARF tumor suppressor. However, the precise linkage between stabilization of ARF tumor suppressor by HuR and shorten telomeres during a replicative senescence is unknown. Here, we show that HuR represses TINF2 (TRF1-Interacting Nuclear Factor 2) through its 3’UTR, and stabilized TINF2 plays a role as driving force to be shorten telomeres during a replicative senescence. We found that loss of HuR induces stabilization of TINF2 mRNA, and stabilized TINF2 induces progressive telomere shortening. Furthermore, facilitated (enforced) telomere shortening by stabilized TINF2 occurs prior to cell cycle arrest via stabilization of the ARF tumor suppressor. Our results demonstrate that progressive telomere shortening are concomitant to stabilization of the ARF tumor suppressor under orchestration of HuR during a replicative senescence.