title: Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease.
abstract: Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD. This is associated with persistent telomeric DNA damage, leading to cellular senescence. CS disrupts the interaction of TPP1 with the Sirtuin 1 (Sirt1) complex, leading to increased TPP1 acetylation and degradation. Lung fibroblasts deficient in Sirt1 or treated with a selective Sirt1 inhibitor exhibit increased cellular senescence and decreased TPP1 levels, whereas Sirt1 overexpression and pharmacological activation protect against CS-induced TPP1 reduction and telomeric DNA damage. Our findings support an essential role of TPP1 in protecting CS-induced telomeric DNA damage and cellular senescence, and therefore provide a rationale for a potential therapy for COPD, on the basis of the shelterin complex, in attenuating cellular senescence.
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Tanveer
authors: T
authors: Ahmad
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Isaac K
authors: IK
authors: Sundar
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Ana M
authors: AM
authors: Tormos
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Chad A
authors: CA
authors: Lerner
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Janice
authors: J
authors: Gerloff
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Hongwei
authors: H
authors: Yao
authors: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Irfan
authors: I
authors: Rahman
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000378:metabolism / Q000473:pathology; D000089804:Shelterin Complex / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; D004268:DNA-Binding Proteins; C440849:POT1 protein, human; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D056564:Sirtuin 1
keywords: Sirtuin1; cellular senescence; emphysema; shelterin complex; telomeric DNA damage