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.
Highlights
Telomeres are evolutionarily conserved nucleoprotein structures at the ends of linear chromosomes
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 accelerated entry into cellular senescence
Summary
Telomeres are evolutionarily conserved nucleoprotein structures at the ends of linear chromosomes. Their primary function is to prevent the cell. Accepted for publication 19 October 2014 from sensing chromosome ends as breaks in double-stranded DNA, thereby suppressing the activation of a DNA damage response (DDR). Telomeres consist of repetitive TTAGG sequences that are associated with shelterin, a six subunit protein complex (Palm & de Lange, 2008), among others. With every division of somatic cells in culture, and presumably in vivo, telomeres progressively shorten by 50–200 bp until one or few telomeres become dysfunctional. The ensuing telomeric DDR typically leads to a permanent proliferative arrest termed cellular senescence or telomere dysfunction-induced cellular senescence (TDIS)
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