Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Román González-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rérolle, Marilyn Tirard, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues Thé () and Valérie Lallemand-Breitenbach ()
Additional contact information
Sarah Tessier: PSL research university, Inserm, Cnrs
Omar Ferhi: PSL research university, Inserm, Cnrs
Marie-Claude Geoffroy: PSL research university, Inserm, Cnrs
Román González-Prieto: Leiden University Medical Center (LUMC)
Antoine Canat: Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis
Samuel Quentin: Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis
Marika Pla: Université de Paris Cité, Inserm, IRSL
Michiko Niwa-Kawakita: Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis
Pierre Bercier: PSL research university, Inserm, Cnrs
Domitille Rérolle: PSL research university, Inserm, Cnrs
Marilyn Tirard: Max Planck Institute of Multidisciplinary Sciences
Pierre Therizols: Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis
Emmanuelle Fabre: Université Paris Cité, Inserm, CNRS, GenCellDis, Institut de Recherche Saint-Louis
Alfred C. O. Vertegaal: Leiden University Medical Center (LUMC)
Hugues Thé: PSL research university, Inserm, Cnrs
Valérie Lallemand-Breitenbach: PSL research university, Inserm, Cnrs

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive. Similarly, PML role in embryonic stem cell (ESC) and retro-element biology is unsettled. Here we demonstrate that PML is essential for oxidative stress-driven partner SUMO2/3 conjugation in mouse ESCs (mESCs) or leukemia, a process often followed by their poly-ubiquitination and degradation. Functionally, PML is required for stress responses in mESCs. Differential proteomics unravel the KAP1 complex as a PML NB-dependent SUMO2-target in arsenic-treated APL mice or mESCs. PML-driven KAP1 sumoylation enables activation of this key epigenetic repressor implicated in retro-element silencing. Accordingly, Pml−/− mESCs re-express transposable elements and display 2-Cell-Like features, the latter enforced by PML-controlled SUMO2-conjugation of DPPA2. Thus, PML orchestrates mESC state by coordinating SUMO2-conjugation of different transcriptional regulators, raising new hypotheses about PML roles in cancer.

Date: 2022
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DOI: 10.1038/s41467-022-33147-6

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