Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage–inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage–induced cell death and hearing loss.

耳蜗毛细胞 （HCs） 感知声波并让我们听到。HCs 的丧失会导致不可逆的感音神经性听力损失。众所周知，DNA 损伤修复在保护许多器官中的细胞方面起着关键作用。然而，HC 如何应对 DNA 损伤以及有缺陷的 DNA 损伤修复如何导致听力损失仍然难以捉摸。在这项研究中，我们发现顺铂诱导外毛细胞 （OHC） 的 DNA 损伤并促进 OHC 损失，导致任何性别的小鼠听力损失。顺铂诱导 OHC 中 Brca1 的表达，这是一种 DNA 损伤修复因子。Brca1 缺乏诱导 OHC 和听力损失，并进一步促进顺铂诱导的 OHC DNA 损伤，加速 OHC 损失。这项研究提供了第一个体内证据，证明顺铂主要诱导 OHC 中的 DNA 损伤，并且 BRCA1 促进 OHC 中 DNA 损伤的修复并防止听力损失。我们的研究结果不仅表明 DNA 损伤诱导剂在有丝分裂后 HCs 中产生 DNA 损伤，而且还表明 DNA 修复因子（如 BRCA1）保护有丝分裂后 HCs 免受 DNA 损伤诱导的细胞死亡和听力损失。