Rationale: The discovery that retinoic acid-related orphan receptor (Rora)-a is highly expressed in lungs of patients with COPD led us to hypothesize that Rora may contribute to the pathogenesis of emphysema. Objectives: To determine the role of Rora in smoke-induced emphysema. Methods: Cigarette smoke extract in vitro and elastase or cigarette smoke exposure in vivo were used to model smoke-related cell stress and airspace enlargement. Lung tissue from patients undergoing lung transplantation was examined for markers of DNA damage and Rora expression. Measurements and Main Results: Rora expression was induced by cigarette smoke in mice and in cell culture. Gene expression profiling of Rora-null mice exposed to cigarette smoke demonstrated enrichment for genes involved in DNA repair. Rora expression increased and Rora translocated to the nucleus after DNA damage. Inhibition of ataxia telangiectasia mutated decreased the induction of Rora. Gene silencing of Rora attenuated apoptotic cell death in response to cigarette smoke extract, whereas overexpression of Rora enhanced apoptosis. Rora-deficient mice were protected from elastase and cigarette smoke induced airspace enlargement. Finally, lungs of patients with COPD showed evidence of increased DNA damage even in the absence of active smoking. Conclusions: Taken together, these findings suggest that DNA damage may contribute to the pathogenesis of emphysema, and that Rora has a previously unrecognized role in cellular responses to genotoxicity. These findings provide a potential link between emphysema and features of premature ageing, including enhanced susceptibility to lung cancer.Keywords: chronic obstructive pulmonary disease; p53; retinoic acidrelated orphan receptor-a; senescence; apoptosis Retinoic acid-related orphan receptor-a (Rora) is a nuclear hormone receptor named for its sequence homology with the retinoic acid receptor; its designation as "orphan" indicates that its natural ligand is unknown. We discovered that Rora expression is robustly increased in lungs of patients with chronic obstructive pulmonary disease (COPD), and this led us to examine whether Rora contributes to the pathogenesis of this disease. Little is known about the role of Rora in the lung, although its absence had been reported to lead paradoxically to increased LPS-induced lung inflammation (1) and decreased allergic inflammation (2). Outside the lung, Rora has been implicated in processes as diverse as osteogenic differentiation (3), circadian rhythm (4), apolipoprotein transcription (5), and Purkinje cell development (6). Gene expression profiling in Rora-null mice led us to the hypothesis that this nuclear receptor is involved in responses to DNA damage.Although the contribution of DNA damage to COPD has not been examined in detail, there are theoretical reasons to believe that genotoxicity could be involved in the pathogenesis of emphysema. Compromised DNA damage repair is known to result in accelerated ageing, as occurs in progeroid syndromes (7). Individuals with these syn...
DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also commonly found in MYC-translocated diffuse large B-cell lymphoma. We reveal functional cooperation between mutant DDX3X and MYC in ex vivo cultured human germinal center B cells. By integrating results of iCLIP, ribosome profiling, and proteomics, we show WT DDX3X promotes the translation of mRNAs encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations act to buffer the effect of abrupt MYC expression and moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells subsequently restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y-chromosome homologue that is normally expressed exclusively in testis. These findings show how sequential dysregulation of DDX3X and DDX3Y acts to titrate global protein synthesis to suit the stage-specific needs of developing lymphoma cells and identify DDX3Y as an attractive, male-specific therapeutic target absent from normal human B cells but required for the survival of male lymphomas. Citation Format: Chun Gong, Joanna A. Krupka, Jane Gao, Nicholas F. Grigoropoulos, Francesco Cucco, Sharon Barrans, De Los Mozos Igor, Zhou Peixun, Forde Sorca, Matthews Jamie, Burke Amos, Sze Siu Kwan, Beer Philip, Burton Cathy, Campbell Peter, Rand Vikki, Turner Suzanne, Ule Jernej, Roman Eve, Tooze Reuben, Oellerich Thomas, Du Ming, Samarajiwa Shamith, Daniel J. Hodson. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-19.
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