Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells
- Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Argentina
- Équipes Labellisées - La Ligue contre le Cancer, France
- Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Argentina
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
Santiago G Miriuka
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
- Michael R Botchan, University of California, Berkeley, United States
Version history
- Received: May 21, 2016
- Accepted: October 7, 2016
- Accepted Manuscript published: October 14, 2016 (version 1)
- 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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Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells
eLife 5:e18020.
https://doi.org/10.7554/eLife.18020
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