G2 DNA damage checkpoint (G2/M checkpoint)

The G2 DNA damage checkpoint is a critical regulatory mechanism in the cell cycle that prevents cells from entering mitosis (M phase) until DNA damage incurred during or before the S phase is repaired [1]. This checkpoint is primarily governed by a signaling cascade involving sensors like ATM and ATR, which activate effector kinases such as CHK1 and CHK2, ultimately inhibiting the CDC25 phosphatase and maintaining the inhibitory phosphorylation of the CDK1/Cyclin B complex by WEE1 [2]. In many cancers, the G1 checkpoint is lost due to TP53 mutations, making these cells uniquely dependent on the G2 checkpoint for survival after DNA damage [3]. Therapeutic strategies often involve inhibiting G2 checkpoint components like WEE1 or CHK1 to force cancer cells into mitotic catastrophe, where they attempt to divide with unrepaired DNA, leading to apoptosis [4]. This approach is particularly effective when combined with DNA-damaging agents like chemotherapy or radiation, or in tumors with specific genetic vulnerabilities like ATM or BRCA deficiency [5]. Current clinical development focuses on small-molecule inhibitors like adavosertib and prexasertib, which aim to exploit this synthetic lethality in p53-deficient tumors [6]. Sources: [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326721/ [2] https://www.nature.com/articles/s41416-019-0435-x [3] https://pubmed.ncbi.nlm.nih.gov/21857671/ [4] https://www.uniprot.org/uniprotkb/P30291/entry [5] https://clinicaltrials.gov/ [6] https://pubchem.ncbi.nlm.nih.gov/compound/Adavosertib

Other names

G2-M DNA damage checkpointG2/M transition checkpointG2/M arrestDNA damage-induced G2/M checkpoint

Inhibition of checkpoint kinases (such as WEE1, CHK1, or ATR) to abrogate the G2 arrest, forcing cells with unrepaired DNA damage into premature mitosis, leading to mitotic catastrophe and apoptosis.