An Update on Nucleolar Stress: The Transcriptional Control of Autophagy

Abstract

Nucleolar stress reflects a misfunction of the nucleolus caused by a failure in ribosome biogenesis and defective nucleolar architecture. Various causes have been reported, most commonly mutation of ribosomal proteins and ribosome processing factors, as well as interference with these processes by intracellular or ectopic stress, such as RNA polymerase I inhibition, ROS, UV and others. The nucleolus represents the place for ribosome biogenesis and serves as a crucial hub in the cellular stress response. It has been shown to stimulate multiple downstream consequences, interfering with cell growth and survival. Nucleolar stress induction is most classically known to stimulate p53-dependent cell cycle arrest and apoptosis. Nucleolar stress represents a friend and enemy at the same time: From a pathophysiological perspective, inactivation of the nucleolar function by mutation or stress conditions is connected to multiple diseases, such as neurodegeneration, cancer and ribosomopathy syndromes. However, triggering the nucleolar stress response via specific chemotherapeutics, which interfere with nucleolar function, has beneficial effects for anti-cancer therapy. Interestingly, since the nucleolar stress response also triggers p53-independent mechanisms, it possesses the potential to specifically target p53-mutated tumors, which reflects the most common aberration in human cancer. More recent data have shown that the nucleolar stress response can activate autophagy and diverse signaling cascades that might allow initial pro-survival mechanisms. Nevertheless, it depends on the situation whether the cells undergo autophagy-mediated apoptosis or survive, as seen for autophagy-dependent drug resistance of chemotherapy-exposed tumor cells. Given the relatively young age of the research field, precise mechanisms that underly the involvement of autophagy in nucleolar stress are still under investigation. This review gives an update on the emerging contribution of nucleolar stress in the regulation of autophagy at a transcriptional level. It also appears that in autophagy p53-dependent as well as -independent responses are induced. Those could be exploited in future therapies against diseases connected to nucleolar stress.

New Insights into Dyskerin-CypA Interaction: Implications for X-Linked Dyskeratosis Congenita and Beyond

“…In addition to its potential involvement in dyskerin-RNP dynamics, we speculate that the nucleolar concentration of CypA might have, per se, a functional relevance for the redox response of this organelle [ 37 ]. In fact, although CypA participates in the maintenance of cell homeostasis in several ways, a significant contribution is given by its ability to act as an endogenous electron donor.…”

WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think

“…Finally, a particularly provocative prediction of a ribosome-directed model for WINi is that the “p53 barrier” to response may not be absolute—a barrier that, if broken, could dramatically expand the utility of these agents. Nucleolar stress is best understood in terms of signaling to p53, but p53-independent nucleolar stress responses do occur [ 91 , 92 , 93 , 94 ]. If these responses can be exposed and therapeutically exploited, the reach of WINi could readily extend to solid tumors and other malignant settings bereft of p53.…”