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Vol. 17, Issue 2, 851-861, February 2006

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Late Activation of Stress Kinases (SAPK/JNK) by Genotoxins Requires the DNA Repair Proteins DNA-PK_cs and CSB

Department of Toxicology, University of Mainz, D-55131 Mainz, Germany

Submitted July 7, 2005; Revised October 31, 2005; Accepted November 17, 2005
Monitoring Editor: J. Silvio Gutkind

Although genotoxic agents are powerful inducers of stress kinases (SAPK/JNK), the contribution of DNA damage itself to this response is unknown. Therefore, SAPK/JNK activation of cells harboring specific defects in DNA damage-recognition mechanisms was studied. Dual phosphorylation of SAPK/JNK by the genotoxin methyl methanesulfonate (MMS) occurred in two waves. The early response (2 h after exposure) was similar in cells knockout for ATM, PARP, p53, and CSB or defective in DNA-PK_cs compared with wild-type cells. The late response however (4 h), was drastically reduced in DNA-PK_cs and Cockayne's syndrome B (CSB)-deficient cells. Similar results were obtained with human cells lacking DNA-PK_cs and CSB. Activation of SAPK/JNK by MMS was not affected upon inhibition of base excision repair (BER), indicating base damage itself does not signal to SAPK/JNK. Because SAPK/JNK activation was attenuated in nongrowing cells, DNA replication-dependent processing of lesions, involving DNA-PK_cs and CSB, appears to be required. DNA-PK_cs coprecipitates with SEK1/MKK4 and SAPK/JNK, supporting a role of DNA-PK_cs in SAPK/JNK activation. In this process, Rho GTPases are involved since inhibition of Rho impairs MMS-induced signaling to SAPK/JNK. The data show that sensing of DNA damage by DNA-PK_cs and CSB causes a delayed SEK1/MKK4-mediated dual phosphorylation of SAPK/JNK.

Address correspondence to: Gerhard Fritz (fritz{at}mail.uni-mainz.de).

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