CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

MANSILLA, SABRINA FLORENCIA; CALZETTA, NICOLÁS LUIS*; DE LA VEGA, MARÍA BELÉN*; SIRI, SEBASTIÁN OMAR*; GOTTIFREDI, VANESA

Genes

MDPI

Lugar: Basel; Año: 2020 vol. 11

p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insuffcient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Viceversa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.*Los co-autores Calzetta, Nicolás Luis; De La Vega, María Belén; Siri, Sebastián Omar contribuyeron equitativamente. El orden en los que aparecen dentro del articulo es: María Belén De La Vega; Nicolás Luis Calzetta; Sebastián Omar Siri.