Division of Animal Sciences, University of Missouri, Columbia, MO, USA.
Department of Physiology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
Nat Commun. 2024 Nov 1;15(1):9463. doi: 10.1038/s41467-024-53559-w.
Unlike mild DNA damage exposure, DNA damage repair (DDR) is reported to be ineffective in full-grown mammalian oocytes exposed to moderate or severe DNA damage. The underlying mechanisms of this weakened DDR are unknown. Here, we show that moderate DNA damage in full-grown oocytes leads to aneuploidy. Our data reveal that DNA-damaged oocytes have an altered, closed, chromatin state, and suggest that the failure to repair damaged DNA could be due to the inability of DDR proteins to access damaged loci. Our data also demonstrate that, unlike somatic cells, mouse and porcine oocytes fail to activate autophagy in response to DNA double-strand break-inducing treatment, which we suggest may be the cause of the altered chromatin conformation and inefficient DDR. Importantly, autophagy activity is further reduced in maternally aged oocytes (which harbor severe DNA damage), and its induction is correlated with reduced DNA damage in maternally aged oocytes. Our findings provide evidence that reduced autophagy activation contributes to weakened DDR in oocytes, especially in those from aged females, offering new possibilities to improve assisted reproductive therapy in women with compromised oocyte quality.
与轻度 DNA 损伤暴露不同，据报道，成熟的哺乳动物卵母细胞暴露于中度或重度 DNA 损伤时，DNA 损伤修复 (DDR) 无效。这种减弱的 DDR 的潜在机制尚不清楚。在这里，我们表明，成熟卵母细胞中的中度 DNA 损伤会导致非整倍体。我们的数据显示，受损的卵母细胞具有改变的、封闭的染色质状态，并表明 DDR 蛋白无法访问受损基因座，可能是由于无法修复受损 DNA。我们的数据还表明，与体细胞不同，小鼠和猪卵母细胞在 DNA 双链断裂诱导处理时不能激活自噬，我们认为这可能是改变染色质构象和低效 DDR 的原因。重要的是，自噬活性在母体老化的卵母细胞（具有严重的 DNA 损伤）中进一步降低，其诱导与母体老化卵母细胞中的 DNA 损伤减少相关。我们的研究结果提供了证据，表明自噬激活减少导致卵母细胞中 DDR 减弱，尤其是在来自年龄较大的女性的卵母细胞中，这为改善因卵母细胞质量受损而进行辅助生殖治疗的女性提供了新的可能性。
