Cells respond to DNA damage by activating protein kinase-mediated signaling pathways that promote cell-cycle arrest, DNA repair, or apoptosis. A key regulator of cell-cycle arrest is the CDC25A (cell division cycle 25 homologue A) phosphatase. CDC25A normally plays a pivotal role in regulating the G1/S and G2/M transitions by dephosphorylating and activating cyclin/cyclin-dependent kinase (CDK) complexes; however, CDC25A is specifically degraded in response to DNA damage. Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation. Taken together, these results indicate that the STK38-mediated phosphorylation of CDC25A at Ser-76 and the subsequent degradation of CDC25A are required to promote DNA damage-induced G2/M checkpoint activation.
Keywords: CDC25A; DNA damage; Degradation; G2/M checkpoint; STK38.
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