CONICET | Buscador de Institutos y Recursos Humanos

p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). Such a p21-mediatedkinase inhibition is not achieved in every cell cycle but is triggered only when cells are subjected to exogenous insults thatcause replication stress and steeply upregulate p21. In such specific conditions, p21 promotes the arrest of cells in the G1 andG2 phases of the cell cycle. As in the absence of exogenous insults, p21 levels are low and insufficient to inhibit CDKs, p21levels in unstressed cells were interpreted to be residual. However, we have demonstrated that such an apparently residualamount of p21 controls nascent DNA elongation speed and origin firing during unstressed replication to preserve genomicstability. Mechanistically, p21 levels during unstressed replication prevent the unscheduled loading of DNA polymerases withlow processivity to replisomes, favoring a normal replication speed. On the other hand, a second report has showed thatendogenous p21 limits nascent DNA elongation. While the mechanism driving the latter contribution of p21-to the control ofDNA replication speed is unknown, a recent report linked the -catenin pathway with the control of p21 levels and thelimitation of the nascent DNA synthesis speed. We are currently attempting to identify the molecular bases of such amechanistic conundrum. We hypothesize that a partial p21 downregulation promotes the utilization of certain drivers of DNAelongation while full p21 elimination favors a second mechanism that displaces the previous one. I will present data thatsupports such a hypothesis and l discuss how we will attempt to explore such hidden hierarchies in the pathways controllingDNA replication in cells.