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.
SIGNIFICANCE STATEMENT: The utility of
cisplatin in
chemotherapy remains limited due to serious side effects, including
sensorineural hearing loss. We show that mouse models of
Cockayne syndrome, a progeroid disorder resulting from a defect in the transcription-coupled DNA repair (TCR) branch of nucleotide excision repair, are hypersensitive to
cisplatin-induced
hearing loss and sensory hair cell death in the organ of Corti, the mammalian auditory sensory epithelium. Our work indicates that Csa and Csb, two genes involved in TCR, are preferentially required to protect against
cisplatin ototoxicity, relative to global genome repair-specific elements of nucleotide excision repair, and suggests that TCR is a major force maintaining
DNA integrity in the cochlea. The
Cockayne syndrome mice thus represent a model for testing the contribution of DNA repair mechanisms to
cisplatin ototoxicity.