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XRCC3 loss leads to midgestational embryonic lethality in mice
DNA Repair ( IF 3.0 ) Pub Date : 2021-09-22 , DOI: 10.1016/j.dnarep.2021.103227
Rohit Prakash 1 , Laina Freyer 2 , Néstor Saiz 3 , Svetlana Gavrilov 4 , Raymond Q Wang 5 , Peter J Romanienko 6 , Elizabeth Lacy 5 , Anna-Katerina Hadjantonakis 5 , Maria Jasin 5
Affiliation  

RAD51 paralogs are key components of the homologous recombination (HR) machinery. Mouse mutants have been reported for four of the canonical RAD51 paralogs, and each of these mutants exhibits embryonic lethality, although at different gestational stages. However, the phenotype of mice deficient in the fifth RAD51 paralog, XRCC3, has not been reported. Here we report that Xrcc3 knockout mice exhibit midgestational lethality, with mild phenotypes beginning at about E8.25 but severe developmental abnormalities evident by E9.0–9.5. The most obvious phenotypes are small size and a failure of the embryo to turn to a fetal position. A knockin mutation at a key ATPase residue in the Walker A box results in embryonic lethality at a similar stage. Death of knockout mice can be delayed a few days for some embryos by homozygous or heterozygous Trp53 mutation, in keeping with an important role for XRCC3 in promoting genome integrity. Given that XRCC3 is a unique member of one of two RAD51 paralog complexes with RAD51C, these results demonstrate that both RAD51 paralog complexes are required for mouse development.



中文翻译:

XRCC3 缺失导致小鼠妊娠中期胚胎死亡

RAD51 旁系同源物是同源重组 (HR) 机制的关键组成部分。已报道四种典型 RAD51 旁系同源物的小鼠突变体,并且这些突变体中的每一种都表现出胚胎致死性,尽管处于不同的妊娠阶段。然而,缺乏第五个 RAD51 旁系同源物 XRCC3 的小鼠的表型尚未见报道。在这里我们报告Xrcc3基因敲除小鼠表现出妊娠中期的致死率,从大约 E8.25 开始具有轻微的表型,但从 E9.0-9.5 开始出现严重的发育异常。最明显的表型是体积小和胚胎无法转为胎位。Walker A 盒中关键 ATP 酶残基的敲入突变导致处于相似阶段的胚胎致死率。对于一些胚胎,通过纯合或杂合的Trp53突变,基因敲除小鼠的死亡可以延迟几天,这与 XRCC3 在促进基因组完整性方面的重要作用保持一致。鉴于 XRCC3 是具有 RAD51C 的两个 RAD51 旁系同源复合物之一的独特成员,这些结果表明这两个 RAD51 旁系同源复合物都是小鼠发育所必需的。

更新日期:2021-10-01
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