Ataxia telangiectasia and Rad3-related protein (ATR) and Checkpoint kinase 1 (Chk1) signaling pathway (ATR-Chk1 pathway)

The Ataxia telangiectasia and Rad3-related protein (ATR) and Checkpoint kinase 1 (Chk1) signaling pathway is a fundamental arm of the DNA damage response (DDR) that maintains genomic integrity during DNA replication. Upon detection of single-stranded DNA (ssDNA) coated by Replication Protein A (RPA) at stalled replication forks or sites of damage, ATR is recruited and activated (UniProt Q13535). ATR then phosphorylates Chk1, which mediates downstream effects including S and G2/M cell cycle arrest, stabilization of replication forks, and inhibition of late origin firing (UniProt O14757). This pathway is frequently exploited in cancer therapy because many tumors possess defects in the ATM-p53 pathway, making them hypersensitive to ATR or Chk1 inhibition (Nature Reviews Cancer, 2021, PMID: 33859377). Small molecule inhibitors targeting these kinases aim to induce replication catastrophe by forcing cells with damaged DNA to undergo premature mitosis (PubMed, PMID: 28273437). Current clinical strategies involve using these inhibitors as monotherapies in patients with specific genetic vulnerabilities or in combination with DNA-damaging chemotherapies and PARP inhibitors to enhance efficacy (NIH NCI, DDR Inhibitors).

Other names

ATR-Chk1 axisRPA-ATR-Chk1 signalingDNA damage response pathwayReplication stress response pathway

Inhibition of ATR or Chk1 kinases prevents the activation of the replication stress response, leading to the collapse of stalled replication forks, accumulation of double-strand breaks, and induction of mitotic catastrophe in cancer cells.