A tumor supresor function of p21 CDKN1A that excedes and precedes cyclin kinase inactivation.

MANSILLA S F, BERTOLIN, AP, BERGOGLIO V, GONZÁLEZ BESTEIRO MA, PILLAIRE MJ, CAZAUX C, HOFFMANN JS, AND GOTTIFREDI V

Congreso; X ALAMCTA Meeting; 2016

Asociación LatinoAmericana de mutagenesis, carcinogénesis y teratogénesis ambiental

A tumor suppressor function of p21CDKN1A that exceeds and precedes cyclin kinase inactivationMansilla, Sabrina F.; Bertolin, Agustina P.; Bergoglio, Valérie, González Besteiro, Marina A., Pillaire, Marie-Jeanne; Cazaux, Christophe; Hoffmann, Jean-Sébastien ; and Gottifredi, VanesaThe 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 is functional and necessary to preserve the genomic stability of unstressed cells. p21 depletion 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.