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#checkpoint control

2 public questions tagged with this topic.

Cell Cycle Regulation

What is the function of the G2 checkpoint?

After DNA replication in S phase, cells must verify that genome was fully and accurately duplicated and that any damage incurred during replication is repaired before segregating chromosomes in mitosis. G2 checkpoint serves this purpose at G2 to M transition, acting as final guardian before entry into prophase driven by CDK1-cyclin B activation. Central regulators include kinases ATR and ATM that sense single-stranded DNA and double-strand breaks, activating CHK1 and CHK2 which phosphorylate and inhibit Cdc25 phosphatase, thereby keeping CDK1 in inactive phosphorylated state bound to 14-3-3 proteins. Additional role involves topoisomerase II sensing incomplete decatenation and p38 MAPK signaling. If damage persists, p53-dependent transcription of GADD45 and 14-3-3 sigma contributes to arrest. Only when repair is complete does Plk1 and Aurora A promote Cdc25 reactivation and CDK1-cyclin B translocation to nucleus, triggering chromosome condensation. Ensuring chromosome segregation fidelity rather than microtubule attachment, which is monitored by spindle checkpoint, distinguishes G2 function, preventing transmission of broken chromosomes and aneuploidy onset.

Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 13: DNA Damage Checkpoints; Hustedt & Durocher, Nature Cell Biol 2006, G2/M Control.

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Cell Cycle Regulation

Which checkpoint prevents cells with damaged DNA from entering S phase?

Cell cycle progression in eukaryotes is guarded by surveillance mechanisms that halt advance when conditions are unfavorable. At transition from G1 to S phase, cell must ensure adequate size, nutrients, growth factor signaling, and integrity of genome before committing to DNA replication, an irreversible step that duplicates entire genetic content. G1 checkpoint, often termed restriction point in mammalian cells, integrates signals from cyclin D-CDK4/6 and cyclin E-CDK2 that phosphorylate retinoblastoma protein Rb, releasing E2F transcription factors driving S-phase genes. If DNA damage, oxidative stress, or insufficient nucleotides are detected, pathways involving p53-induced p21 and CHK2 activate to inhibit CDK2-cyclin E, keeping Rb hypophosphorylated and preventing entry. Double-strand breaks sensed by ATM activate p53 stabilization. Failure of this checkpoint allows replication of damaged templates, increasing mutation rate and chromosomal instability predisposing to cancer. G2 checkpoint instead monitors completion of replication, M checkpoint monitors spindle attachment. Hence G1 checkpoint specifically blocks damaged cells from entering S, preserving genomic stability.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 17: Cell Cycle Control and Checkpoints; Sherr, Science 1996, G1 Progression.

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