Stn1 is critical for telomere maintenance and long‐term viability of somatic human cells

Aging Cell

Virginia Boccardi²  Neetu Razdan⁴  Jessica Kaplunov⁴  Jyoti J. Mundra³  Masayuki Kimura¹  Abraham Aviv¹ 

[1]Center of Human Development and Aging, Rutgers Biomedical and Health Sciences, Newark, NJ, USA

[2]Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Naples, Italy

[3]Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, Newark, NJ, USA

[4]Department of Microbiology, Biochemistry & Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA

关键词: cellular senescence;    CST;    oxidative stress;    Stn1;    telomere dysfunction;    telomere erosion;   

DOI  :  10.1111/acel.12289

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.