Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence

Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.