The G1/S arrest induced by DNA damage has been ascribed to the transcription factor and tumor suppressor protein TP53 (p53). To be effective within minutes after DNA damage, induction of the G1/S block should exploit transcription- and protein synthesis-independent mechanisms (reviewed in Shackelford et al. 1999).
Upon exposure to ultraviolet light (UV) or ionizing radiation (IR), the abundance and activity of the protein phosphatase CDC25A, required for G1/S transition, rapidly decreases in a p53-independent manner (Mailand et al. 2000, reviewed in Teixeira and Reed 2013). The rapid ubiquitin- and proteasome-dependent destruction of CDC25A phosphatase prevents entry of a cell into S phase by maintaining the Cyclin E:CDK2 (CCNE:CDK2) and, to a lesser extent, Cyclin A:CDK2 (CCNA:CDK2) complexes in their inhibitory phosphorylated (p-Y15) form (Mailand et al. 2000, reviewed in Teixeira and Reed 2013). The destruction of CDC25A in response to UV exposure is dependent on CHEK1 (Chk1) activity (Mailand et al. 2000, reviewed in Teixeira and Reed 2013) while CHEK2 (Chk2) contributes to CDC25A destruction in response to IR (Falck et al. 2001, reviewed in Bartek and Lukas 2001). For details, please refer to events "Phosphorylation of CDC25A by CHEK1", "Phosphorylation of CDC25A by CHEK2", and "CHEK1 phosphorylates CHEK2-phosphorylated CDC25A". The CDC25A-dependent G1/S arrest is reversible, allowing cells to repair UV-induced DNA damage before the onset of DNA replication (Mailand et al. 2000, reviewed in Teixeira and Reed 2013).
The overexpression of CDC25A overrides CHEK1-induced G1/S arrest in vitro and has been reported in a subset of aggressive human tumors (Mailand et al. 2000, reviewed in Fernandez-Vidal et al. 2008).
CHEK1- and CDC25A-mediated G1/S arrest precedes TP53/CDKN1A (p53/p21)-mediated G1/S arrest (Mailand et al. 2000, reviewed in Bartek and Lukas).
