Causes and consequences of replication stress

Abstract

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.

Figure 1. Mechanisms of stalled replication fork restart and collapse

(a) The ATR-mediated replication stress response. ATR and its obligate binding partner ATRIP are activated by a primer-template junction at the stalled replication fork, where ATR initiates a signaling cascade primarily mediated by the effector kinase Chk1. This response promotes fork stabilization and restart, while preventing progression through the cell cycle until replication is completed. (b) Mechanisms for the restart / rescue of stalled forks. Replication forks stalled at DNA lesions (shown here on the leading strand, red star) and stabilized by the ATR pathway can restart replication by firing dormant origins, repriming replication, reversing the stalled fork or activating the DNA damage tolerance pathways. Key intermediates in these restart pathways are illustrated. (c) Mechanisms of fork collapse. If stalled forks are not stabilized, or persist for extended periods of time, replication forks will collapse, preventing replication restart. The mechanism by which a replication fork collapses is still ambiguous, and several possibilities are presented here, including dissociation of replisome components, nuclease digestion of a reversed or stalled fork (middle panels) or replication run-off.

Figure 2. Sources of replication stress

There are a number of conditions or obstacles which can slow or stall DNA replication, including limiting nucleotides, DNA lesions, ribonucleotide incorporation, repetitive DNA elements, transcription complexes and/or DNA hybrids, DNA secondary structure, fragile sites, and oncogene-induced stress. Some of the key resolution pathways which are known for each source of stress are indicated in bold.