ArticleMolecular cell2023
UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
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Article in Molecular cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50citing papers in PubMed
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50 citing papers in PubMed, 67 citations in OpenAlex.
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Authors and funding
35 authors at 6 institutions in 2 countries.
Jonathan M TsaiDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jacob D AguirreFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Yen-Der LiDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA.
Jared BrownDepartment of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Vivian FochtFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Lukas KaterFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Georg KempfFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Brittany SandovalDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stefan SchmittFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Justine C RutterDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Pius GalliFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Faculty of Science, University of Basel, Basel, Switzerland.
Colby R SandateFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Jevon A CutlerPediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Charles ZouDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Katherine A DonovanDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Ryan J LumpkinDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Simone CavadiniFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Paul M C ParkDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Quinlan SieversDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Charlie HattonPediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Elizabeth EnerPediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Brandon D RegaladoPediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Micah T SperlingDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Mikołaj SłabickiDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jeonghyeon KimDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Rebecca ZonDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Zinan ZhangDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Peter G MillerCenter for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Roger BelizaireDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Adam S SperlingDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Eric S FischerDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Rafael IrizarryDepartment of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Scott A ArmstrongPediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Nicolas H ThomäFriedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Electronic address: nicolas.thoma@fmi.ch.
Benjamin L EbertDivision of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: benjamin_ebert@dfci.harvard.edu.
Friedrich Miescher Institute · CHHarvard University · USBroad Institute · USDana-Farber Cancer Institute · USBoston Children's Hospital · USCenter for Cancer Research · US
Funding
TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MTargeting SYK Kinase in AMLP50CA206963 · NCI · DANA-FARBER CANCER INST · PI ASTER, JON C. · 2017 to 2021
$10.6MFunctional Genomic Dissection of Refractory AnemiaR01HL082945 · NHLBI · DANA-FARBER CANCER INSTITUTE · PI EBERT, BENJAMIN LEVINE · 2005 to 2022
$6.8MThe role of clonal hematopoiesis in the development and therapy of myeloid malignanciesR35CA253125 · NCI · DANA-FARBER CANCER INST · PI EBERT, BENJAMIN LEVINE · 2020 to 2024
$4.9MData Analysis Tools for Emerging High-Throughput TechnologiesR35GM131802 · NIGMS · DANA-FARBER CANCER INST · PI Rafael Angel Irizarry · 2019 to 2026
$4.1MOncopathology Training ProgramT32CA251062 · NCI · DANA-FARBER CANCER INST · PI JON C. ASTER, KATHLEEN H BURNS · 2020 to 2026
$2.4MCharacterizing a Common Degradation Pathway for Nuclear Hormone ReceptorsDP5OD036132 · OD · BRIGHAM AND WOMEN'S HOSPITAL · PI Jonathan Michael Tsai · 2023 to 2026
$2.2MDevelopment of a generalizable chemo-proteomics screening platform for small molecule degraders applied to HDACsR01CA262188 · NCI · DANA-FARBER CANCER INST · PI FISCHER, ERIC SEBASTIAN · 2022 to 2025
$1.8MDefining mechanisms of thalidomide analog resistanceK08CA252174 · NCI · DANA-FARBER CANCER INST · PI SPERLING, ADAM · 2020 to 2024
$1.3MRole of PPM1D and PPM1D mutations in hematopoiesis and response to stressK08CA263183 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI MILLER, PETER GRANT · 2021 to 2025
$1.1MNCI NIH HHS K08 CA252174NCI NIH HHS K08 CA263183NCI NIH HHS P01 CA066996NCI NIH HHS P50 CA206963NCI NIH HHS R01 CA262188NCI NIH HHS R35 CA253125NCI NIH HHS T32 CA251062NHLBI NIH HHS R01 HL082945NIGMS NIH HHS R35 GM131802NIGMS NIH HHS T32 GM144273NIH HHS DP5 OD036132
Abstract
Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
Indexed as
ChromatinTranscription FactorsHumansLigandsReceptors, Cytoplasmic and NuclearUbiquitin-Protein LigasesUbiquitinsChromatinLigandsReceptors, Cytoplasmic and NuclearTranscription FactorsUbiquitin-Protein LigasesUbiquitinsUBR5 protein, humanHECT-E3 ligasesnuclear receptorsprotein degradationstructural biologyubiquitin ligases
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