NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer
| Autor: | Elad Horwitz, Joanna A. Vuille, Ben S. Wittner, Devon F. Wiley, Xin Hong, Taronish D. Dubash, Shyamala Maheswaran, Kira L. Niederhoffer, Soroush Hajizadeh, Michael S. Lawrence, Shobha Vasudevan, Risa Burr, Linda T. Nieman, Uyen Ho, Adam Langenbucher, Raul Mostoslavsky, Lee Zou, Benjamin Wesley, Richard Y. Ebright, Jia-Min Zhang, Hongshan Guo, Chenyue Lu, Valentine Comaills, Marcus A. Zachariah, Daniel A. Haber, Gabriel Golczer, Brittany A. Reeves, Mehmet Toner |
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| Rok vydání: | 2021 |
| Předmět: |
Genome instability
Indoles Transcription Elongation Genetic Mitosis Antineoplastic Agents Breast Neoplasms Mice SCID Biology medicine.disease_cause Genomic Instability Article Immediate-Early Proteins Mice Inbred NOD Chromosome instability medicine Transcriptional regulation Nuclear Receptor Subfamily 4 Group A Member 1 Tumor Cells Cultured Animals Humans Molecular Biology Gene 3' Untranslated Regions Cell Proliferation Phenylacetates Binding Sites Cancer Cell Biology medicine.disease Chromatin Assembly and Disassembly Neoplastic Cells Circulating Xenograft Model Antitumor Assays Chromatin Cell biology Gene Expression Regulation Neoplastic HEK293 Cells MCF-7 Cells Ectopic expression Female RNA Polymerase II R-Loop Structures Carcinogenesis Proto-Oncogene Proteins c-fos Signal Transduction |
| Zdroj: | Mol Cell |
| ISSN: | 1097-4164 |
| Popis: | Summary Deregulation of oncogenic signals in cancer triggers replication stress. Immediate early genes (IEGs) are rapidly and transiently expressed following stressful signals, contributing to an integrated response. Here, we find that the orphan nuclear receptor NR4A1 localizes across the gene body and 3′ UTR of IEGs, where it inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes immediate dissociation of NR4A1 and a burst of transcriptionally poised IEG expression. Ectopic expression of NR4A1 enhances tumorigenesis by breast cancer cells, while its deletion leads to massive chromosomal instability and proliferative failure, driven by deregulated expression of its IEG target, FOS. Approximately half of breast and other primary cancers exhibit accessible chromatin domains at IEG gene bodies, consistent with this stress-regulatory pathway. Cancers that have retained this mechanism in adapting to oncogenic replication stress may be dependent on NR4A1 for their proliferation. |
| Databáze: | OpenAIRE |
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