Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline.
Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline.
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DOI：
10.1101/gad.341602.120
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发表时间：
2020-12-01
影响因子：
10.5
通讯作者：
Schimenti JC
中科院分区：
文献类型：
--
作者：
Bloom JC;Schimenti JC
在这项研究中，Bloom和Schimenti研究了原始生殖细胞对DNA损伤的反应。利用环境和遗传应激，作者揭示了G1检查点在防止生殖系中复杂突变的积累以及生殖细胞发育过程中DNA损伤反应的分化方面的重要性。在胎儿发育过程中特定的生殖细胞构成了哺乳动物生殖系的基础。这些原始生殖细胞(PGCs)经历了快速的增殖，但与体细胞相比，生殖系对突变积累具有高度的抵抗力。重要的是，尽管内源性或外源性DNA损伤的存在有可能影响PGCs，但这些细胞对应激源的反应鲜为人知。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小鼠暴露于电离辐射(IR)，并评估了PGCs中的DDR。我们的结果表明，在性别决定之前，PGCs缺乏G1细胞周期检查点。此外，雌性和雄性PGCs在性别决定后对IR诱导的DNA损伤的反应也不同。雌性生殖细胞的IR导致生殖细胞分化和减数分裂起始的解偶联，而雄性生殖细胞的IR则表现为抑制piRNA代谢和转座子去抑制。我们还利用全基因组单细胞DNA测序揭示了DNA修复缺陷生殖细胞(Fancm−/−)的遗传挽救会导致突变发生率和偏差的增加。重要的是，我们的工作揭示了对暴露于DNA损伤的PGCs如何变得发育缺陷的新见解，只留下那些基因适合的细胞来建立成年生殖系。
In this study, Bloom and Schimenti examine the response of primordial germ cells to DNA damage. Using both environmental and genetic stresses, the authors reveal the importance of the G1 checkpoint in preventing accumulation of complex mutations in the germline, and the differentiation of the DNA damage response during germ cell development. 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.
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影响因子：
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DOI：
10.1073/pnas.0807297105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Anderson, Ericka L.;Baltus, Andrew E.;Page, David C.
通讯作者：
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