RESUMEN
Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents.
Asunto(s)
Daño del ADN/efectos de los fármacos , Estrés Oxidativo , Neoplasias Pancreáticas/genética , Especies Reactivas de Oxígeno/toxicidad , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/genética , Humanos , Ratones , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Neoplasias Pancreáticas/patología , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Nucleotide excision repair, a general repair mechanism for removing DNA damage, is initiated by dual incisions bracketing the lesion. In procaryotes, the dual incisions result in excision of the damage in 12- to 13-nucleotide-long oligomers, and in eucaryotes they result in excision of the damage in the form of 24- to 32-nucleotide-long oligomers. We wished to find out if Archaea perform excision repair. Using cell extracts from Methanobacterium thermoautotrophicum, we found that this organism removes UV-induced (6-4) photoproducts in the form of 10- to 11-mers by incising the sixth to seventh phosphodiester bond 5' to the damage and the fourth phosphodiester bond 3' to the damage.
