Tolerance to DNA damage is down-regulated at replication forks through PCNA deubiquitylation.
Ponente: Avelino Bueno
Centro de Investigación del Cáncer (CIC-IBMCC)
Fecha: 30/03/2017 - 30/03/2017
Salón de Actos del Centro de Investigación del Cáncer
DNA damage tolerance (DDT) is one of the major pathways that living cells evolved to maintain genome integrity. The tolerance pathway allows cells to bypass deleterious lesions that block replicative DNA polymerases. In eukaryotes tolerance is controlled by ubiquitylation of the DNA replication factor PCNA. While monoubiquitylation of PCNA enhances error-prone translesion synthesis (TLS), PCNA polyubiquitylation promotes an error-free mechanism based on template switching. It was initially thought that DDT occurs during S-phase to facilitate replication completion. However, PCNA ubiquitylation can effectively operate after genome replication, supporting the hypothesis that DDT may work exclusively as a post-replicative mechanism. We have tested this hypothesis again by studying PCNA deubiquitylation in the eukaryotic model organism Saccharomyces cerevisiae. Reversion of PCNA ubiquitylation provides a crucial opportunity for modulating tolerance to DNA damage. However, the timing of PCNA deubiquitylation during the cell cycle, its relative location at replicating chromatin and its contribution to DDT pathway selection have remained unknown to date.