Homologous recombination is reduced in female embryonic stem cells by two active X chromosomes
Homologous recombination is reduced in female embryonic stem cells by two active X chromosomes
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DOI：
10.15252/embr.202052190
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发表时间：
2021-07
期刊：
影响因子：
7.7
通讯作者：
Yuka Tamura;T. Ohhata;Hiroyuki Niida;Satoshi Sakai;C. Uchida;K. Masumoto;F. Katou;A. Wutz;M. Kitagawa
中科院分区：
文献类型：
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作者：
Yuka Tamura;T. Ohhata;Hiroyuki Niida;Satoshi Sakai;C. Uchida;K. Masumoto;F. Katou;A. Wutz;M. Kitagawa
在一些原发性乳腺肿瘤中观察到X连锁基因的重新激活。在女性胚胎干细胞（ESC）中也观察到两条活跃的X染色体，但双剂量的X连锁基因是否会影响DNA修复效率仍不清楚。在这里，我们建立了同基因的女性/男性胚胎干细胞，并表明女性胚胎干细胞更敏感的喜树碱，并具有较低的基因靶向效率比男性胚胎干细胞，这表明同源重组（HR）的效率降低女性胚胎干细胞。我们还产生了Xist可诱导的女性ESC，并表明当X染色体失活被诱导时，较低的HR效率得到恢复。最后，我们评估了X连锁基因在DNA修复中的作用，发现Brcc 3是参与促进适当HR网络的基因之一。我们的研究结果将X连锁基因的双重剂量与较低的DNA修复活性联系起来，这可能与女性患者的常见疾病有关，例如乳腺癌。
The reactivation of X‐linked genes is observed in some primary breast tumors. Two active X chromosomes are also observed in female embryonic stem cells (ESCs), but whether double doses of X‐linked genes affect DNA repair efficiency remains unclear. Here, we establish isogenic female/male ESCs and show that the female ESCs are more sensitive to camptothecin and have lower gene targeting efficiency than male ESCs, suggesting that homologous recombination (HR) efficiency is reduced in female ESCs. We also generate Xist‐inducible female ESCs and show that the lower HR efficiency is restored when X chromosome inactivation is induced. Finally, we assess the X‐linked genes with a role in DNA repair and find that Brcc3 is one of the genes involved in a network promoting proper HR. Our findings link the double doses of X‐linked genes with lower DNA repair activity, and this may have relevance for common diseases in female patients, such as breast cancer.