Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 430 East 67 Street, New York, NY 10065, United States; Regeneron Pharmaceuticals, Tarrytown, New York, NY, United States.
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 430 East 67 Street, New York, NY 10065, United States; Institut Pasteur, Paris, France.
DNA Repair (Amst). 2021 Dec;108:103227. doi: 10.1016/j.dnarep.2021.103227. Epub 2021 Sep 22.
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.
RAD51 同源物是同源重组 (HR) 机制的关键组成部分。已经报道了四种经典 RAD51 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，尽管在不同的胎龄阶段。然而，第五个 RAD51 同源物 XRCC3 缺失的小鼠表型尚未报道。在这里，我们报告 Xrcc3 敲除小鼠表现出中胚层致死性，大约在 E8.25 左右开始出现轻度表型，但在 E9.0-9.5 时明显出现严重的发育异常。最明显的表型是胚胎体积小，不能转为胎儿位置。在 Walker A 盒中的关键 ATP 酶残基上发生的点突变导致在相似的阶段出现胚胎致死性。对于一些胚胎来说，通过 Trp53 突变的纯合或杂合，可以将敲除小鼠的死亡延迟几天，这与 XRCC3 在促进基因组完整性方面的重要作用一致。鉴于 XRCC3 是 RAD51C 两个 RAD51 同源物复合物之一的独特成员，这些结果表明两个 RAD51 同源物复合物都需要用于小鼠发育。
