Primary cilia and cellular senescence (360G-Wellcome-209038_Z_17_Z)

Somatic cells undergo senescence after a finite number of divisions, indefinitely arresting their proliferation. The mechanisms of cellular senescence are not well understood, although DNA damage signalling is one major cause. We have found that senescent human fibroblasts have increased frequency and length of primary cilia, antenna-like structures that sense and transduce various extracellular signals, notably Hedgehog. Here we propose to test the hypothesis that primary ciliation contributes to cellular senescence. We will use genome editing in primary cells to ablate CEP164, which is required for primary ciliogenesis, and then follow the kinetics of cellular senescence in the knockout population. We also propose to examine cilium-controlled signalling pathways to determine how they are affected during the initiation of senescence programmes. We will perform competitive co-culture experiments between ciliated and non-ciliated populations to define how ciliation capacity directs senescence in mixed populations. Together, the proposed experiments will test a novel cellular mechanism of senescence, a process of great significance in human health and the normal aging process.