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Guo H, Golczer G, Wittner BS, et al. NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer. Mol Cell. 2021;81(19):4041-4058.e15doi: 10.1016/j.molcel.2021.09.016.
Guo, H., Golczer, G., Wittner, B. S., Langenbucher, A., Zachariah, M., Dubash, T. D., Hong, X., Comaills, V., Burr, R., Ebright, R. Y., Horwitz, E., Vuille, J. A., Hajizadeh, S., Wiley, D. F., Reeves, B. A., Zhang, J. M., Niederhoffer, K. L., Lu, C., Wesley, B., Ho, U., Nieman, L. T., Toner, M., Vasudevan, S., Zou, L., Mostoslavsky, R., Maheswaran, S., Lawrence, M. S., & Haber, D. A. (2021). NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer. Molecular cell, 81(19), 4041-4058.e15. https://doi.org/10.1016/j.molcel.2021.09.016
Guo, Hongshan, et al. "NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer." Molecular cell vol. 81,19 (2021): 4041-4058.e15. doi: https://doi.org/10.1016/j.molcel.2021.09.016
Guo H, Golczer G, Wittner BS, Langenbucher A, Zachariah M, Dubash TD, Hong X, Comaills V, Burr R, Ebright RY, Horwitz E, Vuille JA, Hajizadeh S, Wiley DF, Reeves BA, Zhang JM, Niederhoffer KL, Lu C, Wesley B, Ho U, Nieman LT, Toner M, Vasudevan S, Zou L, Mostoslavsky R, Maheswaran S, Lawrence MS, Haber DA. NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer. Mol Cell. 2021 Oct 07;81(19):4041-4058.e15. doi: 10.1016/j.molcel.2021.09.016. PMID: 34624217; PMCID: PMC8549465.
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Mol Cell. 2021 Oct 07;81(19):4041-4058.e15. doi: 10.1016/j.molcel.2021.09.016.

NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer.

Molecular cell

Hongshan Guo, Gabriel Golczer, Ben S Wittner, Adam Langenbucher, Marcus Zachariah, Taronish D Dubash, Xin Hong, Valentine Comaills, Risa Burr, Richard Y Ebright, Elad Horwitz, Joanna A Vuille, Soroush Hajizadeh, Devon F Wiley, Brittany A Reeves, Jia-Min Zhang, Kira L Niederhoffer, Chenyue Lu, Benjamin Wesley, Uyen Ho, Linda T Nieman, Mehmet Toner, Shobha Vasudevan, Lee Zou, Raul Mostoslavsky, Shyamala Maheswaran, Michael S Lawrence, Daniel A Haber

Affiliations

  1. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  2. Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  3. Center for Bioengineering in Medicine and Shriners Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  4. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  5. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  6. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
  7. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
  8. Massachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].

PMID: 34624217 PMCID: PMC8549465 DOI: 10.1016/j.molcel.2021.09.016

Abstract

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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: CTCs; IEGs; R-loops; circulating tumor cells; genomic instability; immediate early genes; orphan nuclear receptor; replication stress; transcriptional regulation

Conflict of interest statement

Declaration of interests Massachusetts General Hospital (MGH) has applied for patents regarding the CTC-iChip technology and CTC detection signatures. M.T., D.A.H., and S.M. are cofounders and have eq

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