Nucleolar size regulates nuclear envelope shape in Saccharomyces cerevisiae

ABSTRACTNuclear shape and size are cell-type specific. Change in nuclear shape is seen during cell division, development and pathology. The nucleus of Saccharomycescerevisiae is spherical in interphase and becomes dumbbell shaped during mitotic division to facilitate the transfer of one nucleus to the daughter cell. Because yeast cells undergo closed mitosis, the nuclear envelope remains intact throughout the cell cycle. The pathways that regulate nuclear shape are not well characterized. The nucleus is organized into various subcompartments, with the nucleolus being the most prominent. We have conducted a candidate-based genetic screen for nuclear shape abnormalities in S. cerevisiae to ask whether the nucleolus influences nuclear shape. We find that increasing nucleolar volume triggers a non-isometric nuclear envelope expansion resulting in an abnormal nuclear envelope shape. We further show that the tethering of rDNA to the nuclear envelope is required for the appearance of these extensions.

Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence, and apoptosis. NF-κB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. While nucleolar and NF-κB pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IκB degradation and NF-κB nuclear translocation. Under these stress conditions, the RelA component of NF-κB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly the discuss how crosstalk between nucleoli and NF-κB signalling may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.

NF-kB Nucleoli Crosstalk in Stress Response and the Regulation of Apoptosis

Nucleoli are emerging as key sensors of cellular stress and regulators of the downstream consequences on proliferation, metabolism, senescence and apoptosis. NF-kB signalling is activated in response to a similar plethora of stresses, which leads to modulation of cell growth and death programs. Although these pathways are distinct, it is increasingly apparent that they converge at multiple levels. Exposure of cells to certain insults causes a specific type of nucleolar stress that is characterised by degradation of the PolI complex component, TIF-IA, and increased nucleolar size. Recent studies have shown that this atypical nucleolar stress lies upstream of cytosolic IkB degradation and NF-kB nuclear translocation. Under these stress conditions, the RelA component of NF-kB accumulates within functionally altered nucleoli to trigger a nucleophosmin dependent, apoptotic pathway. In this review, we will discuss these points of crosstalk and their relevance to the anti-tumour mechanism of aspirin and small molecule CDK4 inhibitors. We will also briefly discuss how NF-kB-nucleoli crosstalk may be more broadly relevant to the regulation of cellular homeostasis and how it may be exploited for therapeutic purpose.