DNA damage activates Ataxia telangiectasia mutated (ATM) and/or ATM and Rad3-related (ATR) signaling kinases, which triggers a dual wave of checkpoint responses in the G1-S boundary: (i) ATM and ATR phosphorylates CHEK2 and CHEK1 transducer kinases respectively. Consequently, the CHEK kinase(s) phosphorylates their critical substrate, the CDC25A phosphatase, leading to its rapid ubiquitination and degradation. As the CDC25A role in the progress from G1 to S phase is to activate CDK1/2 (by dephosphorylation of inhibitory phosphorylations of these CDKs), the degradation of Cdc25A leads to halting the cell in G1. The execution of this cascade is relatively quick (20 to 30 minutes) but transient (lasting only several hours). (ii) ATM/ATR phosphorylates (directly or indirectly) both TP53 and its regulatory protein MDM2, which enhance TP53 stability and its DNA binding activity. To achieve G1-S checkpoint arrest, TP53 enhance the transcription of the cyclin-dependent kinase (Cdk) inhibitor p21/WAF1/CIP1 (CDKN1A). The p53-dependent G1-S arrest has been argued to be activated even by a single DNA double-strand break. The p53-dependent G1-S arrest is established slowly because of its transcription dependent. The SWI/SNF chromatin-remodeling complex is involved in the activation of p21(CDKN1A), and GAAD45A - another contributor of the G1-S arrest. ATM-mediated phosphorylation and inhibition of KAP1 (TRIM28) co-repressor enables the elevation of CDKN1A expression. CDKN1A inhibits the CycA-CDK2, CycE-CDK2, and CycB-CDC2 (CDK1) complexes, halting the cell in G1.
