Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A

Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A CDC25A protein, a phosphatase required for progression from G1 to S phase of the cell cycle, is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells (Bernardi et al. 2000).In response to UV light or ionizing radiation (IR), CDC25A in human cells undergoes a rapid ubiquitin- and proteasome-dependent degradation that depends on CHEK1 but not TP53, inducing G1/S arrest that can be bypassed by overexpression of CDC25A (Mailand et al. 2000, reviewed in Teixera and Reed 2013). CHEK2 (Chk2) contributes to CDC25A destruction in response to IR (Falck et al. 2000, 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". Treatment with hydroxyurea, which induces DNA replication stress and can indirectly lead to DNA damage, leads to a marked decrease in CDC25A protein levels in many human cell lines in a ubiquitin- and proteasome-dependent manner and persistent phosphorylation of CDK2 on tyrosine residue Y15 (Molinari et al. 2000). Besides CHEK1 and CHEK2, other kinases that may contribute to phosphorylation of CDC25A that targets it for ubiquitin-mediated degradation in response to DNA damage or replicative stress are PLK3 and GSK3B (Kang et al. 2008). Osmotic stress can also lead to p38 MAPK phosphorylation-dependent ubiquitination and degradation of CDC25A (Goloudina et al. 2003). Phosphorylation of CDC25A by CHEK1 and likely p38 MAPK and GSK3B primes it for additional phosphorylation by kinases such as NEK11 (Melixetian et al. 2009) or Casein kinases I (Honaker and Piwnica-Worms 2010, Piao et al. 2011), which creates a phosphodegron needed for binding to the SCF-BTrCP E3 ubiquitin ligase complex, leading to ubiquitin-mediated degradation of CDC25A (Busino et al. 2003, Jin et al. 2003, reviewed in Teixeira and Reed 2013).