Replication stress and genome rearrangements: lessons from yeast models

Abstract

Replication failures induced by replication fork barriers (RFBs) or global replication stress generate many of the chromosome rearrangement (CR) observed in human genomic disorders and cancer. RFBs have multiple causes and cells protect themselves from the consequences of RFBs using three general strategies: preventing expression of RFB activity, stabilising the arrested replisome and, in the case of replisome failure, shielding the fork DNA to allow rebuilding of the replisome. Yeast models provide powerful tools to understand the cellular response to RFBs, delineate pathways that suppress genome instability and define mechanisms by which CRs occur when these fail. Recent progress has identified key features underlying RFBs activity and is beginning to uncover the DNA dynamics that bring about genome instability.