title: Cyclin Kinase-independent role of p21CDKN1Ain the promotion of nascent DNA elongation in unstressed cells.
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.
authors.affiliation: Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Sabrina F
authors.initials: SF
authors.lastname: Mansilla
authors.affiliation: Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Agustina P
authors.initials: AP
authors.lastname: Bertolin
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.|INSERM, Universite Paul Sabatier-CNRS, Université de Toulouse, Toulouse, France.|Laboratoire d'Excellence TOUCAN, Toulouse, France.|Equipe labellisée La Ligue contre le Cancer, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bergoglio
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.|INSERM, Universite Paul Sabatier-CNRS, Université de Toulouse, Toulouse, France.|Laboratoire d'Excellence TOUCAN, Toulouse, France.|Equipe labellisée La Ligue contre le Cancer, Toulouse, France.
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pillaire
authors.affiliation: Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Marina A
authors.initials: MA
authors.lastname: González Besteiro
authors.affiliation: Laboratorio de Investigaciones Aplicadas en Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Belén de Escobar, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Luzzani
authors.affiliation: Laboratorio de Investigaciones Aplicadas en Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Belén de Escobar, Argentina.
authors.forename: Santiago G
authors.identifier: 0000-0003-2402-3920
authors.initials: SG
authors.lastname: Miriuka
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.|INSERM, Universite Paul Sabatier-CNRS, Université de Toulouse, Toulouse, France.|Laboratoire d'Excellence TOUCAN, Toulouse, France.|Equipe labellisée La Ligue contre le Cancer, Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.|INSERM, Universite Paul Sabatier-CNRS, Université de Toulouse, Toulouse, France.|Laboratoire d'Excellence TOUCAN, Toulouse, France.|Equipe labellisée La Ligue contre le Cancer, Toulouse, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hoffmann
authors.affiliation: Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Vanesa
authors.identifier: 0000-0001-9656-5951
authors.initials: V
authors.lastname: Gottifredi
mesh_terms: D002455:Cell Division; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA
keywords: DNA elongation; DNA replication; cancer biology; cell biology; common fragile site; genomic stability; human; p21 CDKN1A