Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea.
Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, Korea.
J Pineal Res. 2019 Nov;67(4):e12603. doi: 10.1111/jpi.12603. Epub 2019 Aug 22.
Mammalian oocytes remain arrested at the first prophase of meiosis in ovarian follicles for an extended period. During this protracted arrest, oocytes are remarkably susceptible to the accumulation of DNA damage. Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, has diverse effects on various physiological processes. However, the effect of melatonin on DNA damage response in mammalian oocytes has not been explored. Here, we showed that melatonin protected mouse oocytes from DNA damage induced by double-strand breaks (DSBs) during prophase arrest and subsequently improved oocyte quality. We found that DNA damage during prophase arrest impaired subsequent meiotic maturation and deteriorated oocyte quality, increasing chromosome fragmentation, spindle abnormality, mitochondrial aggregation, and oxidative stress. However, melatonin treatment during DNA damage accumulation at prophase improved meiotic maturation and relieved the quality decline of oocytes. In addition, melatonin inhibited the accumulation of DNA damage during prophase arrest by reducing the γ-H2AX levels. Although activated ATM levels were decreased by melatonin treatment, the effect of melatonin on DNA damage response was not a direct consequence of ATM inhibition. Instead, melatonin enhanced DNA repair via nonhomologous end-joining (NHEJ) pathway. Interestingly, these actions of melatonin on DNA damage response are receptor-independent in mouse oocytes. Therefore, our results demonstrated that melatonin protects oocytes from DNA damage during prophase arrest by enhancing DNA repair via NHEJ and subsequently prevents the deterioration of oocyte quality during meiotic maturation.
哺乳动物卵母细胞在卵巢卵泡中处于第一次减数分裂的前期停滞状态，并保持这种停滞状态很长一段时间。在这段长时间的停滞过程中，卵母细胞极易积累 DNA 损伤。褪黑素（N-乙酰-5-甲氧基色胺）是松果腺分泌的一种激素，对各种生理过程有多种影响。然而，褪黑素对哺乳动物卵母细胞中 DNA 损伤反应的影响尚未得到探索。在这里，我们表明褪黑素可保护卵母细胞免受前期停滞期间双链断裂（DSB）引起的 DNA 损伤，并随后改善卵母细胞质量。我们发现，前期停滞期间的 DNA 损伤会损害随后的减数成熟，并降低卵母细胞的质量，增加染色体碎片化、纺锤体异常、线粒体聚集和氧化应激。然而，在前期 DNA 损伤积累期间进行褪黑素处理可改善减数成熟并缓解卵母细胞质量下降。此外，褪黑素通过降低 γ-H2AX 水平来抑制前期停滞期间的 DNA 损伤积累。尽管褪黑素处理会降低激活的 ATM 水平，但褪黑素对 DNA 损伤反应的作用并非 ATM 抑制的直接结果。相反，褪黑素通过非同源末端连接（NHEJ）途径增强 DNA 修复。有趣的是，这些褪黑素对 DNA 损伤反应的作用在小鼠卵母细胞中是受体非依赖性的。因此，我们的研究结果表明，褪黑素通过增强 NHEJ 途径的 DNA 修复来保护卵母细胞免受前期停滞期间的 DNA 损伤，从而防止减数成熟过程中卵母细胞质量的恶化。
