Recovery from the DNA Replication Checkpoint.

Indrajit Chaudhury,Deanna Koepp

doi:10.3390/genes7110094

Abstract

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.

Highlights

The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis
Initiation of the S-phase checkpoint response is dependent on a signaling cascade that is remarkably conserved in eukaryotes
This review will highlight mechanisms identified in simple eukaryotes such as budding yeast and point out distinctions observed in higher eukaryotes, including humans. Both stalled replication forks and DNA damage are recognized by sensor complexes, which activate a kinase cascade to prevent cell cycle progression

Summary

Introduction

The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis. Perturbations in DNA synthesis—such as a scarcity of free nucleotides or damaged DNA—leads to replication fork stalling and activation of the checkpoint pathway [1,2]. As the S-phase checkpoint is sensitive to perturbations even under favorable conditions, it is likely that recovery from checkpoint initiation is critical in each and every cell division. If checkpoint recovery mechanisms fail, stalled forks can persist, increasing the likelihood of DNA damage. If cell cycle resumption mechanisms become uncoupled from checkpoint inactivation, cells with under-replicated DNA would proceed through the cell cycle, impacting genomic stability

Activation of Checkpoint Signaling

Checkpoint Signaling Inactivation

Resumption of DNA Replication

Future Perspectives