title: Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.
abstract: Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Maral E
authors.initials: ME
authors.lastname: Mobasher
authors.affiliation: Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address: falawi@upenn.edu.
authors.forename: Faizan
authors.initials: F
authors.lastname: Alawi
mesh_terms: D017209:Apoptosis; D001859:Bone Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D019871:Dyskeratosis Congenita / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering
keywords: Chloroquine; DNA damage; Dyskeratosis congenita; Histone deacetylase inhibitor; Senescence-associated heterochromatinization; U2OS cells