UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Nuclear hormone receptors (NRs) are critical drug targets.
• Agonist-induced NR degradation is essential for therapeutic efficacy in certain cancers.
• The ubiquitin ligase machinery responsible for NR degradation remains largely unknown.

Purpose of the Study:

• To identify the ubiquitin ligase responsible for agonist-induced NR degradation.
• To elucidate the structural and mechanistic basis of NR degradation by UBR5.
• To understand the role of UBR5 in regulating NR-mediated transcription.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of human UBR5.
• Negative stain electron microscopy to model UBR5 interaction with RARA/RXRA.
• Biochemical assays to assess NR degradation and recruitment dynamics.

Main Results:

• UBR5 was identified as the ubiquitin ligase that degrades multiple agonist-bound NRs, including RARA, RXRA, and others.
• High-resolution cryo-EM structure of UBR5 and a model of its interaction with RARA/RXRA were determined.
• Agonist ligands induce sequential recruitment of coactivators and UBR5 to chromatin.
• Selective estrogen receptor degraders (SERDs) utilize UBR5 or RNF111 for receptor degradation.

Conclusions:

• UBR5 is a central mediator of agonist-induced degradation for a broad range of nuclear hormone receptors.
• UBR5 acts as a transcriptional regulatory hub, linking NR activity to degradation pathways.
• Targeting the UBR5-NR interaction may offer novel therapeutic strategies for NR-driven diseases.