RESUMEN
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
Asunto(s)
Reparación del ADN , Genes BRCA1 , Genes BRCA2 , Mutación/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Ratones , Ratones Desnudos , Modelos Biológicos , Neoplasias/enzimología , Neoplasias/patología , Poli(ADP-Ribosa) Polimerasas/deficiencia , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especificidad por Sustrato , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Prolonged storage of murine leukaemia virus in ambient light leads to a loss of infectivity. Particle integrity and envelope incorporation are unaffected; rather, the defect is functional and intrinsic to the viral core. Light in the violet part of the visible spectrum (wavelength 420-430 nm) is responsible for virus inactivation. Reduced reverse transcriptase-dependent cDNA generation post-entry accounts for the loss in infectivity and is likely due to a polymerase processivity defect. The virion-associated reverse transcription complex is thus photolabile. The phenomenon could be important in certain experimental situations, notably at elevated temperatures or when exposure to light is extensive. Additionally, our study suggests that the reverse transcription complex is a suitable target for an anti-retroviral strategy; identification of the nature of the lesion and the mechanism of its induction may inform the design of novel inhibitors.