CYCLIN-KINASE INDEPENDENT FUNCTIONS OF p21Waf/CIP1 IN THE REGULATION OF THE REPLISOME

CAIMI, LILEN; MANSILLA, SABRINA; CALZETTA, NICOLAS; GOTTIFREDI, VANESA

on-line

Congreso; SAIB - SAMIGE Joint meeting 2021 on line; 2021

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular. Sociedad Argentina de Microbiología General

p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). Such a p21-mediated kinase inhibition is not achieved in every cell cycle but is triggered only when cells are subjected to exogenous insults that cause replication stress and steeply upregulate p21. In such specific conditions, p21 promotes the arrest of cells in the G1 and G2 phases of the cell cycle. As in the absence of exogenous insults, p21 levels are low and insufficient to inhibit CDKs, p21 levels in unstressed cells were interpreted to be residual. However, we have demonstrated that such an apparently residual amount of p21 controls nascent DNA elongation speed and origin firing during unstressed replication to preserve genomic stability. Mechanistically, p21 levels during unstressed replication prevent the unscheduled loading of DNA polymerases with low processivity to replisomes, favoring a normal replication speed. On the other hand, a second report has showed that endogenous p21 limits nascent DNA elongation. While the mechanism driving the latter contribution of p21-to the control of DNA replication speed is unknown, a recent report linked the -catenin pathway with the control of p21 levels and the limitation of the nascent DNA synthesis speed. We are currently attempting to identify the molecular bases of such a mechanistic conundrum. We hypothesize that a partial p21 downregulation promotes the utilization of certain drivers of DNA elongation while full p21 elimination favors a second mechanism that displaces the previous one. I will present data that supports such a hypothesis and l discuss how we will attempt to explore such hidden hierarchies in the pathways controlling DNA replication in cells.