The rDNA transcription occurs at the interface between FCs and dense fibrillary component (DFC), in the latter of which occurs the early processing of precursor ribosomal RNA (rRNA). The fibrillar centers (FCs) contain non-transcribed rDNA and rDNA chromatin associated factors. The nucleoli have a tripartite structure ( Figure 1) with the three substructures functionally separate. The current view thus holds that formation of the nucleoli is a combination of both active recruitment of factors and LLPS.
LLPS has a role in the formation and internal organization of the nucleoli to functional substructures ( Feric et al., 2016). Recently, the role of liquid-liquid phase separation (LLPS) in formation of MLOs has been increasingly recognized ( Shin and Brangwynne, 2017 Sawyer et al., 2018). The nucleoli belong to a group of membraneless organelles (MLOs), and as such, they are dynamic structures with highly mobile constituents that can diffuse in and out to the nucleoplasm. Other anchors for the spatial positioning of the nucleoli are intermediate filament proteins, especially lamins A/C, B1 and B2, that connect the nucleoli to nuclear matrix and contribute to maintaining nucleolar structure and functions ( Martin et al., 2009 Louvet et al., 2014 Matsumoto et al., 2016 Buchwalter and Hetzer, 2017 Sen Gupta and Sengupta, 2017).
DJ sequences have been suggested to anchor rDNA to the PNH ( Mangan et al., 2017). Their sequences are shared between the acrocentric chromosomes and dominated by around 100 kb inverted repeats and seem to have a complex chromatin structure ( Floutsakou et al., 2013 Mangan et al., 2017). The telomeric sides of NORs contain regions called distal junctions (DJs). Yet, what is known is that the sequences on the centromeric side of rDNA are heavily segmentally duplicated and likely do not contain NOR regulatory elements ( Floutsakou et al., 2013 Mangan et al., 2017). Currently, the sequences of the acrocentric arms are missing from human genome drafts. In human cells, the mature nucleoli are associated with perinucleolar heterochromatin (PNH), DNA sequences located distal and proximal to NORs on the acrocentric chromosomal arms ( McStay, 2016), which is likely to contribute to positioning of the nucleoli to the 3D context in the nuclei. In addition, recent evidence of liquid-liquid phase separation (LLPS) and liquid-solid phase transition in the formation of nucleoli and its stress responses, respectively, are discussed, along with the increasingly indicated role and open questions for noncoding RNA species in these events. In this article, the nucleolus as the site of protein and RNA accumulation and as a possible protective organelle for nuclear proteins during stress is viewed.
Yet, the molecular mechanisms governing these processes remain largely undefined. These indicate a relevance of nucleolar function and regulation in neurodegeneration-related cellular events, but also provide surprising connections with cancer-related pathways. This takes place in nucleolar cavities and manifests in protein and RNA collections referred to as intranucleolar bodies (INBs), nucleolar aggresomes or amyloid bodies (A-bodies), depending on stress type, severity of accumulation, and material propensities of the macromolecular collections. The nucleolus serves as an active regulatory site for detention of extranucleolar proteins. In addition to known reactions to DNA damaging and transcription inhibiting stresses, there is an emerging role of the nucleolus especially in responses to proteotoxic stress such as heat shock and inhibition of proteasome function. The nucleolus has a well-established role in ribosome biogenesis and functions in several types of cellular stress responses. This article focuses on the role the nucleolus has as a hub in macromolecule regulation in the mammalian nucleus. Protein- and RNA-containing foci and aggregates are a hallmark of many age- and mutation-related neurodegenerative diseases.
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