Mechanisms of ribosomopathy and phase separation-related ribosomopathy

Abstract

Ribosome is an intracellular ribonucleoprotein particle that serves as the site of protein biosynthesis. Ribosomal dysfunction caused by mutations in genes encoding ribosomal proteins (RPs) and ribosome biogenesis factors (RBFs) can lead to a spectrum of diseases, collectively known as ribosomopathy. Phase separation is a thermodynamic process that produces multiple phases from a homogeneous mixture. The formation of membraneless organelles and intracellular structures, including ribosomes and nucleoli, cannot occur without the involvement of phase separation. Here, ribosome structure, biogenesis, and their relationship with ribosomopathy are systematically reviewed. The tissue specificity of ribosomopathy and the role of phase separation in ribosomopathy are particularly discussed, which may offer some clues for understanding the mechanisms of ribosomopathy. Then, some new ideas for the prevention, diagnosis, and treatment of ribosomopathy are provided.

Keywords: Phase separation; Ribosome; Ribosomopathy; Tissue specificity.

Fig. 1. Intra-nucleolar ribosome biogenesis process and associated ribosomopathies. The red dashed frames highlight the abnormal steps in ribosome biogenesis factors that give rise to several ribosomopathies: Treacher-Collins syndrome (TCS), acrofacial dysostosis-Cincinnati type (AFDCIN), cartilage hair hypoplasia-anauxetic dysplasia (CHH-AD), North American Indian childhood cirrhosis (NAIC), dyskeratosis congenita (DC/DKC), and Bowen-Conradi syndrome (BCS). The legend at the bottom identifies important ribosome biogenesis factors and other components. UBF: upstream-binding factor; Pol I: polymerase I; eIF6: eukaryotic initiation factor 6; rDNA: ribosomal DNA; rRNA: ribosomal RNA.

Fig. 2. Extra-nucleolar ribosome biogenesis process and associated ribosomopathies. This diagram simplifies ribosome biogenesis in the nucleolus. The red dashed frames highlight additional typical ribosomopathies: Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), and 5q-syndrome. The legend at the bottom identifies important ribosome biogenesis factors and other components. rDNA: ribosomal DNA; rRNA: ribosomal RNA; rRNP: ribosomal RNA protein; RPGs: ribosomal protein genes; MDM2: murine double minute 2; mRNA: messenger RNA; RPs: ribosomal proteins; Pol: polymerase; eIF6: eukaryotic initiation factor 6; SBDS: Shwachman-Bodian-Diamond syndrome; EFL1: elongation factor-like GTPase 1; SRP54: signal recognition particle 54 kDa subunit; DNAJC21: DnaJ heat shock protein family (Hsp40) member C21.

Fig. 3. Phase separation in the nucleolar organization and ribosome biogenesis. (a) Inactive Pol I in fibrillar center restricts transcriptionally inactive rDNA to specific regions. (b) The cross-linking of nascent rRNA to rDNA motifs promotes their intercalation with ribonucleoproteins and chromatin-binding proteins, contributing to the formation of mixed droplets. (c) Through multivalent interactions, dense fibrillar component (DFC) with higher surface tension is encapsulated by granular component (GC), functioning as a "production line" to enable efficient rRNA processing and modification. rDNA: ribosomal DNA; rRNA: ribosomal RNA; rRNP: ribosomal RNA protein; FBL: fibrillarin; NPM1: nucleophosmin 1; DDX21: DEAD-box RNA helicase 21; Pol I: polymerase I.