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J. Biol. Chem., Vol. 277, Issue 22, 19358-19366, May 31, 2002

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Oncogenic H-Ras Enhances DNA Repair through the Ras/Phosphatidylinositol 3-Kinase/Rac1 Pathway in NIH3T3 Cells
EVIDENCE FOR ASSOCIATION WITH REACTIVE OXYGEN SPECIES^*

Hyun-Ju Cho^§, Hye Gwang Jeong^§¶, Jung-Sup Lee^§, Eun-Rhan Woo^§¶, Jin-Won Hyun^**, Myung-Hee Chung^**, and Ho Jin You^§

From the  Department of Pharmacology, School of Medicine, the ^§ Research Center for Proteineous Materials, and the Departments of ^¶ Pharmacy and  Biological Sciences, Chosun University, 375 Seosuk-dong, Kwangju 501-759, Korea and the ^** Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Seoul 110-799, Korea

This study investigated the role of oncogenic H-Ras in DNA repair capacity in NIH3T3 cells. Expression of dominant-positive H-Ras (V12-H-Ras) enhanced the host cell reactivation of luciferase activity from UV-irradiated and cisplatin-treated plasmids and also increased the unscheduled DNA synthesis following cisplatin or UV treatment of cells. This observed enhancement of DNA repair capacity was inhibited by transient transfection with dominant-negative H-Ras (N17-H-Ras) or Rac1 (N17-Rac1) plasmids. Moreover, stable transfection of dominant-positive Rac1 (V12-Rac1) further enhanced DNA repair capacity. Because reactive oxygen species (ROS) are known to be a downstream effector of oncogenic Ras, we examined the role of ROS in DNA repair capacity. We found that ROS production by V12-H-Ras expression was mediated by the Ras/phosphatidylinositol 3-kinase (PI3K)/Rac1/NADPH oxidase-dependent pathway and that pretreatment of V12-H-Ras-transformed cells with an antioxidant (N-acetylcysteine) and an NADPH oxidase inhibitor (diphenyleneiodonium) decreased DNA repair capacity. Similarly, treatment with PI3K inhibitors (wortmannin and LY294002) inhibited the ability of oncogenic H-Ras to enhance DNA repair capacity. Furthermore, inhibition of the Ras/PI3K/Rac1/NADPH oxidase pathway resulted in increased sensitivity to cisplatin and UV in V12-H-Ras-expressing NIH3T3 cells. Taken together, these results provide evidence that oncogenic H-Ras activates DNA repair capacity through the Ras/PI3K/Rac1/NADPH oxidase-dependent pathway and that increased ROS production via this signaling pathway is required for enhancement of the DNA repair capacity induced by oncogenic H-Ras.

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