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. 2016 Oct 28;7(11):94.
doi: 10.3390/genes7110094.

Recovery From the DNA Replication Checkpoint

Free PMC article

Recovery From the DNA Replication Checkpoint

Indrajit Chaudhury et al. Genes (Basel). .
Free PMC article


Checkpoint recovery is integral to a successful checkpoint response. Checkpoint pathways monitor progress during cell division so that in the event of an error, the checkpoint is activated to block the cell cycle and activate repair pathways. Intrinsic to this process is that once repair has been achieved, the checkpoint signaling pathway is inactivated and cell cycle progression resumes. We use the term "checkpoint recovery" to describe the pathways responsible for the inactivation of checkpoint signaling and cell cycle re-entry after the initial stress has been alleviated. The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis. When replication stress is encountered, replication forks are stalled, and the checkpoint signaling pathway is activated. Central to recovery from the S-phase checkpoint is the restart of stalled replication forks. If checkpoint recovery fails, stalled forks may become unstable and lead to DNA breaks or unusual DNA structures that are difficult to resolve, causing genomic instability. Alternatively, if cell cycle resumption mechanisms become uncoupled from checkpoint inactivation, cells with under-replicated DNA might proceed through the cell cycle, also diminishing genomic stability. In this review, we discuss the molecular mechanisms that contribute to inactivation of the S-phase checkpoint signaling pathway and the restart of replication forks during recovery from replication stress.

Keywords: DNA replication; S-phase checkpoint; checkpoint recovery; fork restart.

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsor had no role in the writing of the review manuscript.


Figure 1
Figure 1
Diagram of DNA replication checkpoint signaling inactivation mechanisms. (A) During recovery, phosphatases from the PP2A and PP2C families de-phosphorylate Rad53, thus abrogating checkpoint signaling; (B) Competition for binding Rad9 (a Rad53 adaptor) by the Rtt107/Slx4 complex can dampen checkpoint signaling; (C) Ubiquitin-mediated degradation of the Rad53 kinase adaptor Mrc1, facilitated by the SCFDia2 ubiquitin ligase, promotes checkpoint recovery.

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