The G2/M DNA-Damage Checkpoint: ATR, CHK1 and WEE1

What the Checkpoint Protects Against

Entering mitosis with incompletely replicated or broken chromosomes leads to missegregation, chromosome fragments and cell death by mitotic catastrophe. The G2/M checkpoint exists to prevent that outcome.

It integrates two kinds of signal: frank double-strand breaks, sensed mainly through ATM, and replication stress or resected break ends, sensed through ATR.

The Core Signalling Circuit

ATM and ATR phosphorylate the effector kinases CHK2 and CHK1. These in turn inhibit the CDC25 phosphatases, which are needed to activate CDK1, and promote activity of WEE1 kinase, which adds an inhibitory phosphate to CDK1.

The net result is that CDK1-cyclin B stays inactive, cyclin B remains outside the nucleus, and mitotic entry is blocked until repair is complete.

The Contribution of p53

p53 is not required to initiate G2/M arrest, but it helps make the arrest durable by inducing p21 and other targets that keep CDK activity low over hours to days.

Cells without functional p53 can still stop at G2/M acutely, but they struggle to maintain the block and to enforce a stable G1 arrest, shifting their reliance onto the ATR-CHK1-WEE1 circuit.

Turning the Dependency Into a Target

Inhibitors of WEE1 (adavosertib), ATR (ceralasertib, elimusertib) and CHK1 are designed to abolish G2/M arrest in tumour cells that are already carrying damage or replication stress, forcing them into a lethal mitosis.

These agents are still investigational in most contexts, and their effects depend on the tumour's level of replication stress and its remaining checkpoint capacity.

Reading a Report in This Area

Alterations in ATM, ATR, CHEK1, CHEK2 or genes that raise replication stress are sometimes framed as predictive of checkpoint-inhibitor benefit. The supporting evidence is uneven across tumour types and variant classes.

Zygosity, whether an alteration is germline or somatic, and functional context all affect meaning, so a checkpoint-gene finding is a research signal rather than a decision by itself.

Key Takeaways

• ·The G2/M checkpoint keeps CDK1-cyclin B inactive until DNA is repaired and replicated.
• ·ATM/ATR signal through CHK1/CHK2 to inhibit CDC25 and engage WEE1.
• ·p53-deficient tumours are more dependent on this checkpoint.
• ·WEE1, ATR and CHK1 inhibitors exploit that dependency and remain investigational.