Germ cells specified during fetal development form the foundation of the mammalian germline. These primordial germ cells (PGCs) undergo rapid proliferation, yet the germline is highly refractory to mutation accumulation compared with somatic cells. Importantly, while the presence of endogenous or exogenous DNA damage has the potential to impact PGCs, there is little known about how these cells respond to stressors. To better understand the DNA damage response (DDR) in these cells, we exposed pregnant mice to ionizing radiation (IR) at specific gestational time points and assessed the DDR in PGCs. Our results show that PGCs prior to sex determination lack a G1 cell cycle checkpoint. Additionally, the response to IR-induced DNA damage differs between female and male PGCs post-sex determination. IR of female PGCs caused uncoupling of germ cell differentiation and meiotic initiation, while male PGCs exhibited repression of piRNA metabolism and transposon derepression. We also used whole-genome single-cell DNA sequencing to reveal that genetic rescue of DNA repair-deficient germ cells (Fancm^−/−) leads to increased mutation incidence and biases. Importantly, our work uncovers novel insights into how PGCs exposed to DNA damage can become developmentally defective, leaving only those genetically fit cells to establish the adult germline.

中文翻译：

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小鼠种系中的性二态性DNA损伤反应和避免突变

胎儿发育过程中指定的生殖细胞形成了哺乳动物种系的基础。这些原始生殖细胞（PGC）经历了快速增殖，但是与体细胞相比，该种系对于突变积累具有很高的抵抗力。重要的是，虽然内源性或外源性DNA损伤的存在有可能影响PGC，但这些细胞如何对应激源作出反应却鲜为人知。为了更好地了解这些细胞中的DNA损伤反应（DDR），我们在特定的妊娠时间点将怀孕的小鼠暴露于电离辐射（IR）中，并评估了PGC中的DDR。我们的结果表明，性别确定之前的PGC缺少G1细胞周期检查点。此外，性别确定后，雌性和雄性PGC对IR诱导的DNA损伤的反应也不同。雌性PGC的IR引起生殖细胞分化和减数分裂起始的解偶联，而雄性PGC则表现出对piRNA代谢的抑制和转座子抑制。我们还使用了全基因组单细胞DNA测序来揭示DNA修复缺陷生殖细胞的基因拯救（Fancm ^-/-）导致突变发生率和偏倚增加。重要的是，我们的工作揭示了暴露于DNA损伤的PGC如何发展发育缺陷的新见解，仅留下那些遗传上适合的细胞来建立成年种系。