EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2019

EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer

Michel Wassef
  • Fonction : Auteur
Armelle Luscan
  • Fonction : Auteur
Setareh Aflaki
  • Fonction : Auteur
Dina Zielinski
  • Fonction : Auteur
Pascal Jansen
  • Fonction : Auteur
H. Irem Baymaz
  • Fonction : Auteur
Aude Battistella
  • Fonction : Auteur
Carole Kersouani
  • Fonction : Auteur
Nicolas Servant
Margaret Wallace
Pierre Romero
  • Fonction : Auteur
Olivier Kosmider
  • Fonction : Auteur
Pierre-Alexandre Just
  • Fonction : Auteur
Mikaël Hivelin
  • Fonction : Auteur
Sébastien Jacques
  • Fonction : Auteur
Anne Vincent-Salomon
Michiel Vermeulen
  • Fonction : Auteur
Michel Vidaud
  • Fonction : Auteur
Eric Pasmant

Résumé

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2’s main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.

Dates et versions

hal-03951711 , version 1 (23-01-2023)

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Michel Wassef, Armelle Luscan, Setareh Aflaki, Dina Zielinski, Pascal Jansen, et al.. EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (13), pp.6075-6080. ⟨10.1073/pnas.1814634116⟩. ⟨hal-03951711⟩
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