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Peer-reviewedCC BY 4.0Nucleic Acids Research

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

  • Natalie Palkova1
  • Matous Palek1
  • Marketa Brodinova1
  • Zuzana Chalupova1
  • Radka Storchova1
  • Jana Jasprova2
  • Pavel Talacko2
  • Dusan Cmarko3
  • Libor Macurek1
  1. 1Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences , Prague, CZ-14220 ,
  2. 2Proteomics Core Facility, Faculty of Science, Charles University , Prague, CZ-12800 ,
  3. 3Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague , Prague, CZ-12800 ,
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Abstract

The nucleolus is a membrane-less organelle essential for ribosomal DNA (rDNA) transcription and ribosome biogenesis, yet the mechanisms regulating its dynamic assembly remain incompletely understood. Here, we identify the phosphatase protein phosphatase magnesium-dependent 1 delta (PPM1D) as a key regulator of the nucleolar architecture via dephosphorylation of the scaffold protein TCOF1. By combining super-resolution microscopy and domain mapping, we show that PPM1D localizes to the nucleolus through a conserved motif at the C-terminus. Phosphoproteomic analysis and structural modeling revealed that PPM1D targets casein kinase 2 (CK2)-phosphorylated sites within the low-complexity repeat domain of TCOF1, which impacts its interaction with RNA polymerase I (Pol I), immobilization in the fibrillar centres, and nucleolar condensation. Disruption of the phosphorylation balance by loss of PPM1D or inhibition of CK2 leads to nucleolar disorganization and reduced rDNA transcription. Finally, we demonstrate that pharmacological inhibition of PPM1D sensitizes cells to RNA Pol I inhibitors, in both p53-dependent and -independent contexts. Together, we uncover a reversible phosphorylation switch that governs TCOF1 dynamics and its nucleolar function, with potential implications for targeting ribosome biogenesis in cancer.

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Cite

BibTeXRIS
BibTeX
@article{palkova2026dynamic,
  title = {{Dynamic phosphorylation of TCOF1 controlled by CK2 and PPM1D regulates nucleolar condensation and RNA polymerase I activity}},
  author = {Natalie Palkova and Matous Palek and Marketa Brodinova and Zuzana Chalupova and Radka Storchova and Jana Jasprova and Pavel Talacko and Dusan Cmarko and Libor Macurek},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag1060},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1060/9005087},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Dynamic phosphorylation of TCOF1 controlled by CK2 and PPM1D regulates nucleolar condensation and RNA polymerase I activity
AU  - Natalie Palkova
AU  - Matous Palek
AU  - Marketa Brodinova
AU  - Zuzana Chalupova
AU  - Radka Storchova
AU  - Jana Jasprova
AU  - Pavel Talacko
AU  - Dusan Cmarko
AU  - Libor Macurek
PY  - 2026
DA  - 2026/10/01
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag1060
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1060/9005087
AB  - The nucleolus is a membrane-less organelle essential for ribosomal DNA (rDNA) transcription and ribosome biogenesis, yet the mechanisms regulating its dynamic assembly remain incompletely understood. Here, we identify the phosphatase protein phosphatase magnesium-dependent 1 delta (PPM1D) as a key regulator of the nucleolar architecture via dephosphorylation of the scaffold protein TCOF1. By combining super-resolution microscopy and domain mapping, we show that PPM1D localizes to the nucleolus through a conserved motif at the C-terminus. Phosphoproteomic analysis and structural modeling revealed that PPM1D targets casein kinase 2 (CK2)-phosphorylated sites within the low-complexity repeat domain of TCOF1, which impacts its interaction with RNA polymerase I (Pol I), immobilization in the fibrillar centres, and nucleolar condensation. Disruption of the phosphorylation balance by loss of PPM1D or inhibition of CK2 leads to nucleolar disorganization and reduced rDNA transcription. Finally, we demonstrate that pharmacological inhibition of PPM1D sensitizes cells to RNA Pol I inhibitors, in both p53-dependent and -independent contexts. Together, we uncover a reversible phosphorylation switch that governs TCOF1 dynamics and its nucleolar function, with potential implications for targeting ribosome biogenesis in cancer.
SN  - 0305-1048
SN  - 1362-4962
ER  -