The causes of replication stress and their consequences on genome stability and cell fate

Alterations of the dynamics of DNA replication cause genome instability. These alterations known as replication stress have emerged as a major source of genomic instability in pre-neoplasic lesions, contributing to cancer development. The concept of replication stress covers a wide variety of events that distort the temporal and spatial DNA replication program. These events have endogenous or exogenous origins and impact globally or locally on the dynamics of DNA replication. They may arise within a short window of time (acute stress) or during each S phase (chronic stress). Here, we review the known situations in which the dynamics of DNA replication is distorted. We have united them in four main categories: (i) inadequate firing of replication origins (deficiency or excess), (ii) obstacles to fork progression, (iii) conflicts between replication and transcription and (iv) DNA replication under inappropriate metabolic conditions (unbalanced DNA replication). Because the DNA replication program is a process tightly regulated by many factors, replication stress often appears as a cascade of events. A local stress may prevent the completion of DNA replication at a single locus and subsequently compromise chromosome segregation in mitosis and therefore have a global effect on genome integrity. Finally, we discuss how replication stress drives genome instability and to what extent it is relevant to cancer biology. (C) 2014 Elsevier Ltd. All rights reserved.