Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint.
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.
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Takemichi
T
Fukasawa
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: aenomoto-tky@umin.ac.jp.
Atsushi
A
Enomoto
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kiyoshi
K
Miyagawa
D045744:Cell Line, Tumor; D004249:DNA Damage; D004789:Enzyme Activation; D004795:Enzyme Stability; D059565:G2 Phase Cell Cycle Checkpoints / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D012694:Serine; D013997:Time Factors; D014162:Transfection; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D012694:Serine; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
CDC25A; DNA damage; Degradation; G2/M checkpoint; STK38