Dynamic phosphorylation of TCOF1 controlled by CK2 and PPM1D regulates nucleolar condensation and RNA Polymerase I activity

ABSTRACT: The nucleolus is a membrane-less organelle essential for rRNA transcription and ribosome biogenesis, yet the mechanisms regulating its dynamic assembly remain incompletely understood. Here, we identify the phosphatase PPM1D as a key regulator of the nucleolar architecture via dephosphorylation of the scaffold protein TCOF1. PPM1D localizes to the nucleolus through a conserved motif at the C-terminus and targets CK2-phosphorylated sites within the low-complexity repeat domain of TCOF1. These phosphorylation events promote TCOF1 condensation, immobilization in the fibrillar centres, and interaction with the RNA polymerase I, supporting rRNA transcription. Disruption of the phosphorylation balance by loss of PPM1D or inhibition of CK2 impairs TCOF1 function, leading to nucleolar disorganization and reduced rRNA transcription. Structural modelling supports a phosphorylation-dependent interaction between TCOF1 and POLR1A. Furthermore, we demonstrate that pharmacological inhibition of PPM1D sensitizes cells to RNA polymerase I inhibitors, in both p53-dependent and independent contexts. Together, these findings uncover a reversible phosphorylation switch that governs TCOF1 dynamics and its nucleolar function, with potential implications for targeting ribosome biogenesis in cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Pavel Talacko  

LAB HEAD: Libor Macurek

PROVIDER: PXD065997 | Pride | 2026-10-02

REPOSITORIES: Pride