title: Stn1 is critical for telomere maintenance and long-term viability of somatic human cells.
abstract: Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.
authors: Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Naples, Italy.
authors: Virginia
authors: V
authors: Boccardi
authors: Neetu
authors: N
authors: Razdan
authors: Jessica
authors: J
authors: Kaplunov
authors: Jyoti J
authors: JJ
authors: Mundra
authors: Masayuki
authors: M
authors: Kimura
authors: Abraham
authors: A
authors: Aviv
authors: Utz
authors: U
authors: Herbig
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; D019098:Telomerase
keywords: CST; Stn1; cellular senescence; oxidative stress; telomere dysfunction; telomere erosion