The p53 target, p21, triggers a DNA replication-associated cell death which is mediated by its interaction with PCNA

GOTTIFREDI V

Karlsruhe

Workshop; 2 nd German p53 workshop.; 2019

The p53 target, p21, triggers a DNA replication-associated cell death which is mediated by its interaction with PCNAMaría Belén de la Vega, Sabrina Mansilla, Marina Gonzalez Besteiro, Nicolas Calzetta and Vanesa Gottifredi The cyclin kinase inhibitor p21 is the most responsive target of the p53 tumor suppressor. As such, it is the key effector of the arrest triggered by p53 in the G1 and G2 phases of the cell cycle. We have demonstrated that levels of p21 which are residual for cyclin-dependent kinase inhibition are still sufficient to exert functions unrelated to cell cycle arrest. In fact, within S phase, the ?residual? p21 levels interact with the sliding platform for DNA polymerases, PCNA. Such a PCNA-p21 interaction efficiently prevents the loading of specialized DNA polymerases to PCNA and favors nascent DNA elongation by more processive DNA polymerases. Conversely, when cells are UV irradiated and damaged DNA templates accumulate, p21 is degraded in S phase, facilitating DNA replication across DNA lesions in charge of specialized DNA polymerases. The use of a stable version of p21 persistently impairs both the recruitment of specialized DNA polymerases to replication factories and the elongation of nascent DNA, triggering cell death. Moreover, we have identified the minimal version of p21 capable of binding PCNA, preventing the loading of specialized DNA polymerases to DNA and improving UV-triggered cell death. Such a peptide also boosts cancer cell killing after many genotoxins and replication stressing agents that cause accumulation of replication barriers. Hence, the interference of the PCNA interaction with partners such as the specialized DNA polymerases could improve previously approved cancer treatments.