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#G2 checkpoint

3 public questions tagged with this topic.

Cell Division

Which checkpoint ensures that DNA replication is complete before mitosis begins?

Coordination between DNA replication and mitosis is enforced by G2/M checkpoint which prevents nuclear envelope breakdown and chromosome condensation while replication forks still active or lesions persist. Sensor proteins ATRIP recognizes RPA-coated single-stranded DNA at stalled forks, activating ATR kinase, while MRN complex recruits ATM at double-strand breaks. These apical kinases phosphorylate mediator Claspin and adaptor proteins that activate Chk1 and Chk2 kinases. Chk1 phosphorylates phosphatases Cdc25B and Cdc25C at serine 216 creating binding site for 14-3-3 proteins sequestering them in cytoplasm, away from nuclear cyclin B-CDK1 target, preserving inhibitory phosphorylation placed by Wee1. Additionally p53 transcriptional program elevates p21, 14-3-3 sigma, and Gadd45 that bind and inhibit cyclin B-CDK1. Upon completion of replication and successful lesion repair via homologous recombination, checkpoint signaling silences, PP2A reverses phosphorylations, Cdc25 translocates into nucleus and dephosphorylates CDK1, driving explosive activation and mitotic entry after genome duplicated. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Bartek & Lukas, Nature 2003, G2/M Checkpoint Control. Lodish 9th ed., Chapter 20.

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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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