A role for Xrcc2 in the early stages of mouse development
A role for Xrcc2 in the early stages of mouse development
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DOI：
10.1016/j.dnarep.2006.10.024
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发表时间：
2007-02-04
期刊：
影响因子：
3.8
通讯作者：
Thacker, John
中科院分区：
文献类型：
--
作者：
Adam, Julie;Deans, Bryan;Thacker, John
Xrcc 2是五个Rad 51样基因家族之一，在哺乳动物中通过同源重组（HR）修复DNA损伤中具有重要作用。我们之前已经表明，小鼠中Xrcc 2的缺失会导致严重但可变的发育缺陷和胚胎死亡，可能与过度凋亡有关。为了研究致死性的原因，并可能使Xrcc 2（-/-）小鼠存活至出生，我们产生了p53癌蛋白或共济失调毛细血管扩张突变（Atm）缺陷的双敲除小鼠。总体而言，我们表明，在Xrcc 2（-/-）胚胎中观察到的过度凋亡是p53依赖性的，p53的缺失可以恢复培养物中Xrcc 2（-/-）成纤维细胞的生长能力，但它不能挽救胚胎致死性。此外，尽管Xrcc 2（-/-）Trp 53（-/-）胚胎显示出接近正常的形态，但它们的尺寸仍然相对较小。在Xrcc 2（-/-）胚胎中Atm的丧失几乎没有影响，这表明在小鼠发育的早期阶段，对HR能力丧失的反应不是通过Atm激酶介导的。此外，正如早期发育标志物Delta样1的表达减少所示，正常发育程序在Xrcc 2（-/-）胚胎组织中受到干扰，特别是在神经发生和体节发生期间。总之，我们的数据表明，在HR缺陷的胚胎中自发损伤的积累对哺乳动物的发育和存活具有严重的后果，这是由于对发育程序重要的细胞的不受调节的损失。(c)2006 Elsevier B. V.保留所有权利。
Xrcc2 is one of a family of five Rad51-like genes with important roles in the repair of DNA damage by homologous recombination (HR) in mammals. We have shown previously that loss of Xrcc2 in mice results in severe but variable developmental defects and embryonic lethality, potentially linked to excessive apoptosis. To look at the causes of lethality, and possibly to allow Xrcc2(-/-) mice to survive to birth, we have produced double knockout mice deficient in either the p53 oncoprotein or Ataxia telangiectasia mutated (Atm). Overall we show that the excessive apoptosis observed in Xrcc2(-/-) embryos is p53-dependent, and that loss of p53 can restore growth capacity to Xrcc2(-/-) fibroblasts in culture, but that it cannot rescue the embryonic lethality. Additionally, although the Xrcc2(-/-)Trp53(-/-) embryos show a near-normal morphology they remain relatively small in size. Loss of Atm in an Xrcc2(-/-) embryo has little effect, suggesting that response to loss of HR capacity is not mediated through the Atm kinase in the early stages of mouse development. Further, as seen by reduced expression of the early developmental marker, Delta-like1, the normal developmental programme is perturbed in Xrcc2(-/-) embryonic tissues, particularly during neurogenesis and somitogenesis. Taken together our data suggest that the accumulation of spontaneous damage in HR-deficient embryos has severe consequences for the development and survival of mammals due to the unregulated loss of cells important to the developmental programme. (c) 2006 Elsevier B.V. All rights reserved.