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PML Nuclear Bodies are stress-responsive sumoylation/degradation compartments regulating KAP1 silencing function in embryonic stem cells

ABSTRACT: PML drives the assembly of PML Nuclear Bodies (NBs), where it recruits many serendipitously-identified proteins, including the SUMO-E2 enzyme UBC9. Interferons, arsenic or oxidative stress, all enhance NB-formation. Here demonstrate that PML is required for efficient basal sumoylation in mouse embryonic stem cells (mESCs) and immediate stress-responsive sumoylation in mouse liver or Acute Promyelocytic Leukemia (APL). Biochemically, PML NBs confer an oxidation-protective environment for the redox-sensitive UBC9 activity, which, together with enzyme/target concentration/immobilization, favors processive SUMO2/3 conjugation. Accordingly, PML-facilitated sumoylation is accompanied by ubiquitination and degradation of some targets. In vivo proteomic analysis of SUMO2 conjugates in APL identified therapy-responsive targets, among which the prominent KAP1 complex of epigenetic regulators. In mESCs, PML is required for SUMO-dependent KAP1 repressive activity and for the resulting silencing of transposable elements and 2-cell-like genes. The ES status is further regulated by a PML-facilitated repressive sumoylation of the Dppa2 zygote genome activation driver. These findings establish the biochemical function of PML NBs in vivo and unveiling an unsuspected epigenetic control of key ESC targets by PML.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Román González-Prieto

LAB HEAD: Alfred C.O. Vertegaal

PROVIDER: PXD019609 | Pride | 2022-09-14

REPOSITORIES: Pride

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