Smurfs regulate mesendoderm differentiation through Smad2-dependent ubiquitination of CDK9

ABSTRACT: Smurf1 and Smurf2 are HECT-domain E3 ubiquitin ligases classically characterized as negative regulators of TGF-β signaling through ubiquitination of receptors and receptor-associated Smads. Whether Smurfs also regulate transcriptional output at the level of elongation has not been addressed. Here, we show that Smurf1 and Smurf2 attenuate Smad2-driven transcription by ubiquitinating CDK9. Smurf deficiency enhances CDK9 activity, increases CDK9 occupancy immediate downstream of TSS of Smad2-target genes, promotes transcription elongation at Smad2-targeted genes, and prolongs mesendoderm gene expression during differentiation. These findings uncover a previously unrecognized mechanism linking ubiquitin-mediated regulation to transcriptional elongation control and establish Smurfs as key modulators of morphogen-dependent lineage specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE324590 | GEO | 2026/09/28

REPOSITORIES: GEO