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

MANSILLA SF, BETOLIN AP, BERGOGLIO V, PILLAIRE MJ, GONZALEZ M, LUZZANI C, MIRIUKA S, CAZAUX C, HOFFMANN JS, GOTTIFREDI V

eLife

eLife

Lugar: Cambridge; Año: 2016

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