TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells

  1. Katerina Leonova
  2. Alfiya Safina
  3. Elimelech Nesher
  4. Poorva Sandlesh
  5. Rachel Pratt
  6. Catherine Burkhart
  7. Brittany Lipchick
  8. Ilya Gitlin
  9. Costakis Frangou
  10. Igor Koman
  11. Jianmin Wang
  12. Kirill Kirsanov
  13. Marianna G Yakubovskaya
  14. Andrei V Gudkov
  15. Katerina Gurova  Is a corresponding author
  1. Roswell Park Cancer Institute, United States
  2. Buffalo BioLabs, United States
  3. Ariel University, Israel
  4. Blokhin Cancer Research Center, Russian Federation

Abstract

Cellular Responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anti-cancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.

Data availability

The following data sets were generated
    1. Katerina Gurova
    (2017) Effect of CBL0137 on gene expression in mouse cells and tissues
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE102768).

Article and author information

Author details

  1. Katerina Leonova

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alfiya Safina

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elimelech Nesher

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8326-5535
  4. Poorva Sandlesh

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rachel Pratt

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Catherine Burkhart

    Buffalo BioLabs, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brittany Lipchick

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ilya Gitlin

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Costakis Frangou

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Igor Koman

    Department of Molecular Biology, Ariel University, Ariel, Israel
    Competing interests
    The authors declare that no competing interests exist.
  11. Jianmin Wang

    Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kirill Kirsanov

    Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  13. Marianna G Yakubovskaya

    Department of Chemical Carcinogenesis, Blokhin Cancer Research Center, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  14. Andrei V Gudkov

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Katerina Gurova

    Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
    For correspondence
    katerina.gurova@roswellpark.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9189-0712

Funding

National Cancer Institute (RO1CA197967)

  • Katerina Gurova

National Cancer Institute (R21CA198395)

  • Katerina Gurova

Russian Science Foundation (17-15-01526)

  • Marianna G Yakubovskaya

Roswell Park Cancer Center (P30CA016056)

  • Katerina Gurova

Incuron LLC

  • Katerina Gurova

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

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado School of Medicine, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#1093M) of Roswell Park Cancer Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments of Roswell Park Cancer Institute.

Version history

  1. Received: July 28, 2017
  2. Accepted: February 4, 2018
  3. Accepted Manuscript published: February 5, 2018 (version 1)
  4. Version of Record published: February 16, 2018 (version 2)
  5. Version of Record updated: February 21, 2018 (version 3)

Copyright

© 2018, Leonova 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. Katerina Leonova
  2. Alfiya Safina
  3. Elimelech Nesher
  4. Poorva Sandlesh
  5. Rachel Pratt
  6. Catherine Burkhart
  7. Brittany Lipchick
  8. Ilya Gitlin
  9. Costakis Frangou
  10. Igor Koman
  11. Jianmin Wang
  12. Kirill Kirsanov
  13. Marianna G Yakubovskaya
  14. Andrei V Gudkov
  15. Katerina Gurova
(2018)
TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells
eLife 7:e30842.
https://doi.org/10.7554/eLife.30842

Share this article

https://doi.org/10.7554/eLife.30842

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