Causes and Consequences of Replication Stress

(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.

Publication

Causes and Consequences of Replication Stress. () Michelle K. Zeman, et al. Nat Cell Biol. ;16(1):2-9. Figure: F1. All organisms Homo sapiens Danio rerio

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