Ataxia telangiectasia and Rad3-related protein-Checkpoint kinase 1-Cell division cycle 25A-Cyclin-dependent kinase 2 pathway (ATR-CHK1-CDC25A-Cdk2 pathway)

The Ataxia telangiectasia and Rad3-related protein-Checkpoint kinase 1-Cell division cycle 25A-Cyclin-dependent kinase 2 (ATR-CHK1-CDC25A-Cdk2) pathway is a fundamental signaling axis in the DNA damage response (DDR) that coordinates cell cycle progression with DNA repair and replication integrity [1, 3, 5]. ATR acts as the primary sensor for single-stranded DNA and replication stress, subsequently activating the effector kinase CHK1 [1, 9]. Once activated, CHK1 phosphorylates the phosphatase CDC25A, leading to its rapid degradation via the proteasome [3, 6]. The depletion of CDC25A prevents the activation of Cdk2, which effectively halts the cell cycle in S-phase or at the G2/M transition to prevent the replication of damaged DNA [5, 13]. In oncology, this pathway is a major therapeutic target, particularly for tumors that exhibit 'replication stress' or defects in other DDR components like p53 or ATM [3, 10, 16]. Inhibiting ATR or CHK1 disrupts this checkpoint, causing the stabilization of CDC25A and the premature, aberrant activation of Cdk2 [2, 7]. This forces cancer cells to proceed through the cell cycle despite genomic damage, leading to massive DNA breakage, replication fork collapse, and ultimately mitotic catastrophe [2, 8]. Several small-molecule inhibitors of ATR and CHK1 are currently in clinical development, both as monotherapies and in combination with DNA-damaging agents to enhance their cytotoxic effects [1, 9, 15].

Other names

ATR-CHK1 axisATR-CHK1-CDC25A pathwayIntra-S checkpoint pathwayDNA replication stress response pathway

Inhibition of ATR or CHK1 prevents the degradation of CDC25A, leading to aberrant Cdk2 activation, which causes replication stress, DNA damage, and mitotic catastrophe in cancer cells.