Recovery from the DNA Replication Checkpoint

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.

Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells

“…Indeed, the nocodazole- [67] and hydroxyurea-induced [68] cell cycle arrests have been linked to the activation of the PARP-signalling pathways [69,70]. Global changes in gene expression profiles were consistent with the changes in the biological states of the cells, revealing up-regulation of genes involved in cell cycle arrest, development, differentiation and energy reserve metabolic processes and down-regulation of genes associated with metabolic and cell signaling pathways, ion transport and cell adhesion (Supplemental Figures S4 and S5).…”

Role of MCM2–7 protein phosphorylation in human cancer cells

“…Blocks DNA replication through inactivation of MCM complex [ 20 , 46 – 49 , 51 ] MCM7 Cdk2/CycE, Cdk1/CycB S121 Promotes MCM complex formation. Regulates S checkpoint activation and mitotic exit [ 13 ] MCM2 ATR S108 Responds to replication stress and stabilizes replication forks [ 39 ] ATR S108 Responds to replication stress [ 38 ] MCM3 ATM S535 Responds to replication stress [ 38 ] ATM, ATR S728 Responds to replication stress [ 58 ] MCM6 ATR S13 Responds to replication stress [ 59 ] MCM2 SIK1 Unclear Activates helicase activity of MCM complex during DNA replication [ 61 ] MCM3 DAPK S160 Unclear [ 62 ] MCM4 EBV-PK T19, T110 Blocks DNA replication through inactivation of DNA unwinding by the MCM4/6/7 complex. Leads to cell growth arrest [ 26 ] MCM7 ...…”

The Role of the Transcriptional Response to DNA Replication Stress

“…Following the resolution of replication stress, DNA replication must be completed through a number of different replication restart mechanisms, discussed in detail in [21,85]. Following short periods of stress, a stalled fork may be restarted via remodelling by helicases.…”

“…Following checkpoint inactivation, DNA replication must be restarted; the mechanism signalling this has not been fully established [85,121]. The βTrCP-dependent degradation of Claspin is required for efficient termination of Chk1-dependent checkpoint signalling and subsequent recovery of cell cycle progression [122,123].…”