Replication stress response mechanisms by stalling and breakage of replication forks

Description

coordinated firing and progression of multiples replication forks, which are dynamic and fragile structures prompt to stall or break as a consequence of their encounter with DNA lesions and physical obstacles. These situations can compromise the correct and timing completion of chromosome duplication, leading to mutations and genome rearrangements. Genetic instability during DNA replication is associated with cancer, genetic disorders and aging. To mitigate the harmful effects of replication stress, cells possess a variety of mechanisms aimed at stabilizing, protecting, and restarting damaged forks These processes are becoming increasingly understood, offering insights into cellular responses to DNA damage and genome integrity maintenance. Two important aspects are still unclear: 1) the molecular response to DNA lesions and obstacles in function of their position in the template strand for leading or lagging DNA synthesis. This difference might determine the choice of the DNA damage tolerance mechanism, either translesion synthesis (error-prone) or homologous recombination (error-free), thereby affecting the mutagenic impact of the response; 2) the molecular response to broken replication forks, either by direct breakage or encounter with a DNA nick, which is a common intermediate in DNA repair and topological processes targeted in cancer therapies. Our previous work has uncovered a number of genes involved in these responses. In this project, we have designed different systems in the model organism Saccharomyces cerevisiae to dilucidate the genetic and molecular requirements of these processes. Given the evolutionary conservation of genome integrity mechanisms and cell cycle regulation from yeast to humans, the insights gained from this study are expected to generate novel hypotheses regarding the molecular causes of cell cycle dysregulation and the accumulation of genomic rearrangements in cancer and genetic disorders.

Project investigators

• José Felix Prado Velasco – Principal Investigator

Funding entities

Ministerio de Ciencia, Innovación y Universidades