IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation

  1. Li Pan
  2. Madeleine E Lemieux
  3. Tom Thomas
  4. Julia M Rogers
  5. Colin H Lipper
  6. Winston Lee
  7. Carl Johnson
  8. Lynette M Sholl
  9. Andrew P South
  10. Jarrod A Marto
  11. Guillaume O Adelmant
  12. Stephen C Blacklow
  13. Jon C Aster  Is a corresponding author
  1. Brigham and Women's Hospital, United States
  2. Bioinfo, Canada
  3. Harvard Medical School, United States
  4. Thomas Jefferson University, United States
  5. Dana-Farber Cancer Institute, United States
  6. Dana Farber Cancer Institute, United States
  7. Harvard, United States

Abstract

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55a subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE156488 and GSE156624

The following data sets were generated

Article and author information

Author details

  1. Li Pan

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  2. Madeleine E Lemieux

    Bioinfo, Ontario, Canada
    Competing interests
    No competing interests declared.
  3. Tom Thomas

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  4. Julia M Rogers

    Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Colin H Lipper

    Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Winston Lee

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  7. Carl Johnson

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  8. Lynette M Sholl

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  9. Andrew P South

    Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, United States
    Competing interests
    No competing interests declared.
  10. Jarrod A Marto

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Guillaume O Adelmant

    Oncologic Pathology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Stephen C Blacklow

    Department of Biological Chemistry and Molecular Pharmacology, Harvard, Boston, United States
    Competing interests
    Stephen C Blacklow, SCB is on the SAB for Erasca, Inc., receives sponsored research funding from Novartis and Erasca, Inc, and is a consultant for IFM therapeutics and Ayala Pharmaceuticals..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6904-1981
  13. Jon C Aster

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    For correspondence
    jaster@rics.bwh.harvard.edu
    Competing interests
    Jon C Aster, JCA is a consultant for Ayala Pharmaceuticals and for Cellestia, Inc. There is no conflict of interest with the work described in this manuscript..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1957-9070

Funding

Ludwig Institute for Cancer Research (None)

  • Jon C Aster

National Institutes of Health (R35 CA220340)

  • Stephen C Blacklow

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Apurva Sarin, Institute for Stem Cell Science and Regenerative Medicine, India

Version history

  1. Received: April 20, 2020
  2. Accepted: September 15, 2020
  3. Accepted Manuscript published: September 16, 2020 (version 1)
  4. Version of Record published: October 1, 2020 (version 2)

Copyright

© 2020, Pan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Li Pan
  2. Madeleine E Lemieux
  3. Tom Thomas
  4. Julia M Rogers
  5. Colin H Lipper
  6. Winston Lee
  7. Carl Johnson
  8. Lynette M Sholl
  9. Andrew P South
  10. Jarrod A Marto
  11. Guillaume O Adelmant
  12. Stephen C Blacklow
  13. Jon C Aster
(2020)
IER5, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation
eLife 9:e58081.
https://doi.org/10.7554/eLife.58081

Share this article

https://doi.org/10.7554/eLife.58081

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