Biology subjects

Geoffroy, M.-C.

Publications and source records attributed to Geoffroy, M.-C..

2 recordsLinked to original sources

bioRxiv2026

PML-driven sumoylation of PML/RARA-bound co-repressors drives immortalization of primary hematopoietic progenitors

While acute promyelocytic leukemia (APL) is always driven by fusions involving one of the three retinoic acid receptors, why PML and RARA are the preferred fusion partners has remained largely unsettled. Here we demonstrate that corepressor (NCoR) binding onto the RARA moiety of PML/RARA is required for hematopoietic progenitor immortalization. We then establish that PML-mediated tethering of the UBC9 SUMO conjugating enzyme onto PML/RARA enforces SUMO2 conjugation of multiple RARA partner proteins, notably the NCoR complex, boosting its repressive power. PML mutants that fail to recruit UBC9 yield PML/RARA fusions that neither promote NCoR sumoylation nor transformation. Conversely, direct UBC9/RARA fusion drives both efficient NCoR sumoylation and immortalization. Sumoylation inhibitors re-activate retinoic acid target genes in PML/RARA-, but not RARA-, expressing progenitors and trigger APL differentiation. Thus, fusion of PML to RARA entails an unexpected key gain of function that boosts RARA-mediated transcriptional repression through sumoylation of PML/RARA-bound protein, explaining the recurrent implication of PML and RARA in APL pathogenesis.

cancer biology↗

bioRxiv2021

Unbiased in vivo exploration of nuclear bodies-enhanced sumoylation reveals that PML orchestrates embryonic stem cell fate

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, but their role in pluripotency remains elusive. Here we establish that PML is required for basal SUMO2/3 conjugation in mESCs and oxidative stress-driven sumoylation in mESCs or in vivo. PML NBs create an oxidation-protective environment for UBC9-driven SUMO2/3 conjugation of PML partners, often followed by their poly-ubiquitination and degradation. Differential in vivo proteomics identified several members of the KAP1 complex as PML NB-dependent SUMO2-targets. The latter drives functional activation of this key epigenetic repressor. Accordingly, Pml-/- mESCs re-express transposable elements and display features of totipotent-like cells, a process further enforced by PML-controlled SUMO2-conjugation of DPPA2. Finally, PML is required for adaptive stress responses in mESCs. Collectively, PML orchestrates mESC fate through SUMO2-conjugation of key transcriptional or epigenetic regulators, raising new mechanistic hypotheses about PML roles in normal or cancer stem cells.

cell biology↗