Extended Data Fig. 10: Detailed model illustrating how nucleolar Pol-II-dependent R-loops shield the IGS from sincRNA synthesis by Pol I.
From: Nucleolar RNA polymerase II drives ribosome biogenesis
Top and centre, Pol II at rDNA intergenic spacers (IGSs) synthesizes antisense intergenic ncRNAs (asincRNAs) that constitutively engage in R-loops containing DNA–RNA hybrids (orange). Centre, nucleolar Pol II function is promoted by the neurodegeneration-linked SETX protein (purple). Within rRNA genes, the formation of R-loops usually inhibits the function of Pol I, which is subject to Pol II-independent termination. However, disruption of nucleolar Pol II or its R-loops enables the recruitment of Pol I to IGSs. There, Pol I synthesizes sense intergenic ncRNAs (sincRNAs; green) that mimic environmental stress, disrupting nucleolar liquid–liquid phase separation and triggering an aberrant nucleolar liquid-to-solid phase transition. This unscheduled activation of nucleolar stress responses compromises the natural organization of nucleoli, leading to defects in pre-rRNA biogenesis, especially at the processing level. Nucleolar sincRNA levels are naturally elevated in Ewing sarcoma cells, explaining the indistinct nucleoli often seen in this cancer. In the context of Pol II inhibition, SETX loss or Ewing sarcoma, sincRNA repression ameliorates nucleolar organization and rRNA biogenesis.
