Mutations in cockayne syndrome-associated genes (Csa and Csb) predispose to cisplatin-induced hearing loss in mice
The Journal of Neuroscience , Volume 36 - Issue 17 p. 4758- 4770
Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Progressive sensorineural hearing loss is observed in a subset of NER-associated DNA repair disorders including Cockayne syndrome and some forms of xeroderma pigmentosum. We investigated whether either of the two overlapping branches that encompass NER, transcription-coupled repair or global genome repair, which are implicated in Cockayne syndrome and xeroderma pigmentosum group C, respectively, modulates cisplatin-induced hearing loss and cell death in the organ of Corti, the auditory sensory epithelium of mammals. We report that cochlear hair cells and supporting cells in transcription-coupled repair-deficient Cockayne syndrome group A (Csa−/−) and group B (Csb−/−) mice are hypersensitive to cisplatin, in contrast to global genome repair-deficient Xpc−/− mice, both in vitro and in vivo. We show that sensory hair cells in Csa−/− and Csb−/− mice fail to remove cisplatin-DNA adducts efficiently in vitro; and unlike Xpc−/− mice, Csa−/− and Csb−/− mice lose hearing and manifest outer hair cell degeneration after systemic cisplatin treatment. Our results demonstrate that Csa and Csb deficiencies predispose to cisplatin-induced hearing loss and hair/supporting cell damage in the mammalian organ of Corti, and emphasize the importance of transcription-coupled DNA repair in the protection against cisplatin ototoxicity.
|Cisplatin, Cockayne syndrome, DNA repair, Hearing loss, Ototoxicity, Sensory hair cells|
|The Journal of Neuroscience|
|Organisation||Department of Molecular Genetics|
Rainey, R.N, Ng, S.-Y, Llamas, J, van der Horst, G.T.J, & Segil, N. (2016). Mutations in cockayne syndrome-associated genes (Csa and Csb) predispose to cisplatin-induced hearing loss in mice. The Journal of Neuroscience, 36(17), 4758–4770. doi:10.1523/JNEUROSCI.3890-15.2016