"Genome stability during chromosome replication can be challenged by drugs affecting fork progression and intra-S DNA damage. While the mechanisms preserving the integrity of replicating chromosomes in response to replication stress induced by exogenous genotoxic events have been widely studied (Branzei and Foiani 2005; Branzei and Foiani 2007), those controlling fork stability under unperturbed conditions are less understood. Specialized networks control the collision between replication forks and transcription; preventing recombinogenic events. The host laboratory has contributed to elucidate the regulatory processes controlling the integrity of replication forks in response to genotoxic events and the architectural pathway protecting chromosome integrity by coordinating DNA replication and transcription. The overarching aim of this proposal is to understand the mechanisms coordinating replication fork progression across transcribed units using budding yeast as a model organism and a combination of mechanistic, genetic and genomic approaches. The first objective would be to identify and characterize the Mec1 and Rad53-mediated checkpoint mechanisms that control fork stability at transcribed regions while the second is to study whether the checkpoint influences the Top2-mediated epigenetic mechanism coordinating S phase transcription. The rationale of the present project is based on the observations that i) transcribed regions cause fork pausing and the collision between replication forks and transcription bubbles is highly coordinated ii) the replication checkpoint response controls the stability of paused forks iii) replication termination is influenced by transcription iv) oncogene activation leads to massive transcription deregulation and replication stress. The expected findings should have important implications for elucidating the cellular mechanisms preventing genome instability and those pathological processes causing genome rearrangements and cancer."
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