Causes and consequences of replication stress

Defects in DNA replication, or in the pathways evolved to correct DNA replication problems, can cause genomic instability and disease. Zeman and Cimprich discuss recent advances in our understanding of the cellular responses to replication stress. Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.