Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are important therapeutic targets in malignancy. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant: the oncogenic PML-RARA fusion between PML and the retinoic acid receptor (RARA) drives acute promyelocytic leukemia and degradation of PML-RARA induced by all-trans-retinoic acid (ATRA) is required for anti-tumor activity. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones. Overall design: RNA sequencing (RNA-seq) was performed for NB4 and A549 cells. Samples were prepared and sequenced in biological duplicate across multiple times following treatment. Treatment consisted of application of ATRA (NB4 cells) or Dexamethasone (A549 cells). For each cell type, 2 control genotypes (2 knockdowns of luciferase) and two test genotypes (2 typs of UBR5 knockdown) were parepared for each treatment condition.