ATMATRsignalveier

ATM and ATR signaling pathways are essential components of the cellular response to DNA damage and replication stress. They belong to the family of PIKK kinases and coordinate early detection, signal amplification, and the choice of DNA repair or cell cycle arrest to preserve genomic integrity.

ATM is primarily activated by DNA double-strand breaks through the MRN complex (MRE11-RAD50-NBS1). Upon activation, ATM autophosphorylates and dissociates from inactive dimers, triggering phosphorylation of key targets such as CHK2, p53, and BRCA1. ATR responds mainly to replication stress and single-stranded DNA coated with RPA, recruited by ATRIP; its activation is facilitated by factors like TOPBP1 and ETAA1. Once active, ATR phosphorylates CHK1, BRCA1, and other substrates, coordinating a replication checkpoint and promoting DNA repair processes.

Downstream effects of ATM and ATR signaling include stabilization of stalled forks, transcriptional changes, and cell cycle arrest to allow repair. ATM-CHK2-p53 signaling can induce G1/S arrest, while ATR-CHK1 signaling governs S-phase and G2/M checkpoints. H2AX phosphorylation (γ-H2AX) marks sites of damage and helps recruit repair proteins. Repair pathways engaged under these signals include non-homologous end joining, homologous recombination, nucleotide excision repair, and processing of replication-associated lesions.

Biological significance and clinical relevance are prominent. Defects in ATM can cause ataxia-telangiectasia and increased cancer risk, while ATR mutations are linked to developmental disorders. In cancer therapy, inhibitors of ATR or ATM are explored as radiosensitizers or chemosensitizers, exploiting synthetic lethality with defects in BRCA1/2 or other DNA repair genes. The pathways also interact with other damage responses, reflecting a coordinated network to maintain genomic stability.