Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice.
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.



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.
Department of Stem Cell Biology and Regenerative Medicine, and Caruso Department of Otolaryngology, University of Southern California, Eli and Edythe Broad Center, Los Angeles, California 90033, and.
Robert N
0000-0003-2732-493X
RN
Rainey
Department of Stem Cell Biology and Regenerative Medicine, and Caruso Department of Otolaryngology, University of Southern California, Eli and Edythe Broad Center, Los Angeles, California 90033, and.
Sum-Yan
SY
Ng
Department of Stem Cell Biology and Regenerative Medicine, and Caruso Department of Otolaryngology, University of Southern California, Eli and Edythe Broad Center, Los Angeles, California 90033, and.
Juan
J
Llamas
Department of Genetics, Cancer Genomic Center, Erasmus MC, Rotterdam 3015 CN, The Netherlands.
Gijsbertus T J
GT
van der Horst
Department of Stem Cell Biology and Regenerative Medicine, and Caruso Department of Otolaryngology, University of Southern California, Eli and Edythe Broad Center, Los Angeles, California 90033, and nsegil@med.usc.edu.
Neil
N
Segil
D000818:Animals; D016923:Cell Death; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000378:metabolism; D003057:Cockayne Syndrome / Q000235:genetics*; D018736:DNA Adducts; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D045643:DNA Repair Enzymes; D002945:Cisplatin
Cockayne syndrome; DNA repair; cisplatin; hearing loss; ototoxicity; sensory hair cells