The role of nucleotide excision repair in cisplatin chemotherapy-induced deafness

2014-08-29We are able to hear because of our ability to transform mechanical vibrations of sound waves into electrical impulses, which our brains can interpret as sound. The conversion is performed by some highly specialized sensory receptors known as sensory hair cells within our inner ear. Despite the significance of these cells to our sensation and survival, humans are not able to regenerate sensory hair cells. We are born with a limited number of sensory hair cells. Any damage to these cells is irreversible and will lead to permanent hearing loss. It is not fully understood why mammalian hair cells do not regenerate, which severely limits attempts to treat hearing loss in the millions of people affected every year. Hearing loss and hair cell damage can be caused by aging, disease, exposure to loud noise, or chemicals. This project focuses on the hearing loss as a result of exposure to a common chemotherapy drug, cisplatin. ❧ Cisplatin is an effective chemotherapeutic agent, yet it often causes permanent hearing loss, among other side effects. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Mutations in the NER pathways give rise to diseases such as Cockayne syndrome (CS) and xeroderma pigmentosum (XP), which are associated with progressive sensorineural hearing loss. The connections between cisplatin treatment, NER mutations and hearing loss led us to investigate whether defects in NER modulate cisplatin-induced sensory hair cell death and hearing loss in mammals. ❧ This study examines the ototoxic effects of cisplatin-induced DNA damage using mouse models that carry specific mutations in the NER pathway. In order to isolate the impact of the different sub-pathways of NER, we used the Csa, Csb and the Xpc mouse models. The Csa and Csb mice carry mutations that affect the transcription-coupled damage detection step in the NER pathway; the Xpc animal carries a mutation which affects damage detection in the global genome repair sub-pathway of NER. Our results show that disrupting the transcription-coupled repair genes, Csa or Csb, increases the ototoxic effects of cisplatin: profound hearing loss, and extensive cell death in the organ of Corti in mice, both in vivo and in vitro. This suggests that the transcription-coupled NER damage detection step is required to protect hearing and guard sensory hair cells from cisplatin-induced damage. ❧ The project is further extended to understand the role of NER in sensory hair cell regeneration in the mutant models. A number of barriers to regeneration have been identified and tested with limited in vivo success, yet no prior study has examined the involvement of DNA repair in hair cell regeneration. We found that deficiency in the NER pathway appears to limit the effectiveness of hair cell production through supporting cell transdifferentiation in an in vitro model at the early post-natal stage. This implies that NER may play a role in enabling sensory hair cell regeneration in vitro. ❧ We hope that further research along this line of questioning will help reduce ototoxic side effects of cisplatin treatment, and improve the efficiency of current regeneration protocols