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Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells

  1. Sabrina F Mansilla
  2. Agustina P Bertolin
  3. Valérie Bergoglio
  4. Marie-Jeanne Pillaire
  5. Marina A González Besteiro
  6. Carlos Luzzani
  7. Santiago G Miriuka
  8. Christophe Cazaux
  9. Jean-Sébastien Hoffmann
  10. Vanesa Gottifredi  Is a corresponding author
  1. Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Argentina
  2. Équipes Labellisées - La Ligue contre le Cancer, France
  3. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Argentina
Research Article
  • Cited 16
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Cite this article as: eLife 2016;5:e18020 doi: 10.7554/eLife.18020

Abstract

The levels of the cyclin-dependent kinase (CDK) inhibitor p21 are low in S phase and insufficient to inhibit CDKs. We show here that endogenous p21, instead of being residual, it is functional and necessary to preserve the genomic stability of unstressed cells. p21depletion slows down nascent DNA elongation, triggers permanent replication defects and promotes the instability of hard-to-replicate genomic regions, namely common fragile sites (CFS). The p21's PCNA interacting region (PIR), and not its CDK binding domain, is needed to prevent the replication defects and the genomic instability caused by p21 depletion. The alternative polymerase kappa is accountable for such defects as they were not observed after simultaneous depletion of both p21 and polymerase kappa. Hence, in CDK-independent manner, endogenous p21 prevents a type of genomic instability which is not triggered by endogenous DNA lesions but by a dysregulation in the DNA polymerase choice during genomic DNA synthesis.

Article and author information

Author details

  1. Sabrina F Mansilla

    Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  2. Agustina P Bertolin

    Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  3. Valérie Bergoglio

    Équipes Labellisées - La Ligue contre le Cancer, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Marie-Jeanne Pillaire

    Équipes Labellisées - La Ligue contre le Cancer, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Marina A González Besteiro

    Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  6. Carlos Luzzani

    Laboratorio de Investigaciones Aplicadas en Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Belén de Escobar, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  7. Santiago G Miriuka

    Laboratorio de Investigaciones Aplicadas en Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Belén de Escobar, Argentina
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2402-3920
  8. Christophe Cazaux

    Équipes Labellisées - La Ligue contre le Cancer, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean-Sébastien Hoffmann

    Équipes Labellisées - La Ligue contre le Cancer, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Vanesa Gottifredi

    Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires, Argentina
    For correspondence
    vgottifredi@leloir.org.ar
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9656-5951

Funding

National Institutes of Health (R03 TW008924)

  • Vanesa Gottifredi

Agencia Nacional de Promoción Científica y Tecnológica (PICT-2012-1371)

  • Vanesa Gottifredi

Agencia Nacional de Promoción Científica y Tecnológica (PICT-2013-1049)

  • Vanesa Gottifredi

Company of Biologists (Travel Fellowship)

  • Sabrina F Mansilla

Laboratoire d'Excellence Toulouse Cancer LABEX TOUCAN

  • Jean-Sébastien Hoffmann

La Ligue Nationale contra le Cancer

  • Jean-Sébastien Hoffmann

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

Reviewing Editor

  1. Michael R Botchan, University of California, Berkeley, United States

Publication history

  1. Received: May 21, 2016
  2. Accepted: October 7, 2016
  3. Accepted Manuscript published: October 14, 2016 (version 1)
  4. Version of Record published: November 23, 2016 (version 2)

Copyright

© 2016, Mansilla 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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