Date of this Version
Biochemical and Biophysical Research Communications
Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array offundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita. Conversely, wild-type dyskerin is overexpressed in sporadiccancers, and high-levels may be associated with poor prognosis. It was previously reported thatacute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation oftransformed cell lines. However, the mechanisms remained unclear. Using human U2OSosteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescenceas evidenced by proliferative arrest, senescence-associated heterochromatinization and asenescence-associated molecular profile. Senescence can render cells resistant to apoptosis.Conversely, chromatin relaxation can reverse the repressive effects of senescence-associatedheterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis wassuppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation,including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitizeddyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex andplays an important role in telomere homeostasis. Defective telomere maintenance resulting inpremature senescence is thought to primarily underlie the pathogenesis of X-linked DC. SinceU2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function canalso induce cellular senescence via mechanisms independent of telomere shortening.
© <2014>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Senescence-associated heterochromatinization; dyskeratosis congenita; DNA damage; U2OScells; chloroquine; histone deacetylase inhibitor
Lin, P., Mobasher, M. E., & Alawi, F. (2014). ACUTE DYSKERIN DEPLETION TRIGGERS CELLULARSENESCENCE AND RENDERS OSTEOSARCOMA CELLSRESISTANT TO GENOTOXIC STRESS-INDUCED APOPTOSIS. Biochemical and Biophysical Research Communications, 446 (4), 1268-1275. http://dx.doi.org/10.1016/j.bbrc.2014.03.114
Date Posted: 01 March 2022
This document has been peer reviewed.