Nuclear Condensation of NUP98-Fusion Proteins drives leukemogenic gene expression NUP98-fusion protein drive oncogenic gene expression via nuclear/biomolecular condensation
Ontology highlight
ABSTRACT: NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.
INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood Cell, Blood
DISEASE(S): Acute Myeloid Leukemia
SUBMITTER: Andre Mueller
LAB HEAD: Florian Grebien
PROVIDER: PXD022518 | Pride | 2020-12-23
REPOSITORIES: Pride
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