Hsia Kan-Tai, Millar Michael R, King Sasha, Selfridge Jim, Redhead Nicola J, Melton David W, Saunders Philippa T K
Institute of Cell and Molecular Biology, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
Development. 2003 Jan;130(2):369-78. doi: 10.1242/dev.00221.
Ercc1 is essential for nucleotide excision repair (NER) but, unlike other NER proteins, Ercc1 and Xpf are also involved in recombination repair pathways. Ercc1 knockout mice have profound cell cycle abnormalities in the liver and die before weaning. Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype. To investigate the importance of the recombination repair functions of Ercc1 we studied spermatogenesis and oogenesis in Ercc1-deficient mice. Male and female Ercc1-deficient mice were both infertile. Ercc1 was expressed at a high level in the testis and the highest levels of Ercc1 protein occurred in germ cells following meiotic crossing over. However, in Ercc1 null males some germ cell loss occurred prior to meiotic entry and there was no evidence that Ercc1 was essential for meiotic crossing over. An increased level of DNA strand breaks and oxidative DNA damage was found in Ercc1-deficient testis and increased apoptosis was noted in male germ cells. We conclude that the repair functions of Ercc1 are required in both male and female germ cells at all stages of their maturation. The role of endogenous oxidative DNA damage and the reason for the sensitivity of the germ cells to Ercc1 deficiency are discussed.
Ercc1对于核苷酸切除修复（NER）至关重要，但与其他NER蛋白不同的是，Ercc1和Xpf也参与重组修复途径。Ercc1基因敲除小鼠的肝脏存在严重的细胞周期异常，并在断奶前死亡。随后，Xpa和Xpc基因敲除已被证明是人类NER缺陷疾病——着色性干皮病的良好模型，这引发了一种推测，即重组而非NER缺陷是Ercc1基因敲除表型的关键。为了研究Ercc1重组修复功能的重要性，我们研究了Ercc1缺陷小鼠的精子发生和卵子发生。雄性和雌性Ercc1缺陷小鼠均不育。Ercc1在睾丸中高水平表达，并且在减数分裂交叉后，生殖细胞中Ercc1蛋白水平最高。然而，在Ercc1基因敲除的雄性小鼠中，一些生殖细胞在进入减数分裂之前就发生了丢失，并且没有证据表明Ercc1对于减数分裂交叉是必不可少的。在Ercc1缺陷的睾丸中发现DNA链断裂水平增加和氧化性DNA损伤增加，并且在雄性生殖细胞中观察到凋亡增加。我们得出结论，在雄性和雌性生殖细胞成熟的所有阶段都需要Ercc1的修复功能。本文还讨论了内源性氧化性DNA损伤的作用以及生殖细胞对Ercc1缺陷敏感的原因。
