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Nascent Pre-rRNA Sorting via Phase Separation Drives Assembly of Dense Fibrillar Components in Human Nucleolus
 
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A research group led by Dr. CHEN Lingling at Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences reported a most recent progress on nucleolar ultrastructure and nascent pre-rRNAs sorting. They showed the ultrastructure of the nucleolus in live human cells and demonstrated that nascent pre-rRNA sorting via phase separation drives the assembly of dense fibrillar components (DFCs) in the nucleolus. The study was published in Molecular Cell. 

 

Like proteins, the functions of RNAs are associated with unique trafficking pathways and subcellular localization. The mammalian nucleolus is assembled around nucleolar organizer regions (NORs) which are comprised of three morphologically distinct sub-regions named fibrillar center (FC), DFC and granular component (GC). It is believed that such nucleolar ultrastructures are products of the functions they perform that allows continuous Pol I transcription within the FC and the subsequent radial flux of rRNAs through the DFC into the GC and finally into the nucleoplasm. 

 

This system provides an attractive model to address how directional RNA sorting is achieved in cells. However, the compact and electron-dense nature of the nucleolus and the limitation of electron microscopy approaches in determination of individual protein localization have allowed only limited features of the sub-nucleolar organization to be revealed. 

 

In this study, the researchers firstly visualized nucleolar ultrastructures in live cells by different types of super resolution microscopy and mathematic modelling. 

 

They demonstrated that a human cell nucleolus consists of dozens of FC/DFC units that are formed around the rDNA tandem repeats. Each FC/DFC contains 2-3 copies of active rDNAs at the border of FC/DFC where Pol I complexes are located and Pol I transcription occurs. Pre-rRNA processing factors, including FBL, form on average 18-24 clusters that are further assembled into shell like DFC in three dimensions. Formation of such clusters can increase the local concentration of processing factors for efficient pre-rRNA processing. 

 

Furthermore, the researchers showed that FBL self-association plays a key role in controlling the 5' terminus of nascent pre-rRNA movement from the border of FC/DFC to DFC both in vitro and in vivo. 

 

FBL is a key component of the BoxC/D snoRNP involved in pre-rRNA modification and processing. This study uncovers new function of FBL in pre-rRNA sorting and processing. Binding and sorting of 47S pre-rRNA utilizes different FBL domains. Such pre-rRNA sorting strongly correlates with FBL self-association via IDRs and is required for pre-rRNA processing, revealing important functional relevance of this previously under-appreciated sorting process. 

 

Meanwhile, such a phase separation mechanism-controlled pre-rRNA sorting process is required for DFC nucleation, providing a new insight into the mechanism of assembly of cellular membrane-less condensates.   

 

These findings represented an advance in the understanding of the nucleolar spatial organization and how IDRs contribute to nascent pre-rRNA sorting and processing. 

 

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