Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Paul Gerson Unna Group "Skin Homeostasis and Ageing," Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.
Dev Cell. 2019 Jul 22;50(2):167-183.e8. doi: 10.1016/j.devcel.2019.06.012.
Genome integrity in primordial germ cells (PGCs) is a prerequisite for fertility and species maintenance. In C. elegans, PGCs require global-genome nucleotide excision repair (GG-NER) to remove UV-induced DNA lesions. Failure to remove the lesions leads to the activation of the C. elegans p53, CEP-1, resulting in mitotic arrest of the PGCs. We show that the eIF4E2 translation initiation factor IFE-4 in somatic gonad precursor (SGP) niche cells regulates the CEP-1/p53-mediated DNA damage response (DDR) in PGCs. We determine that the IFE-4 translation target EGL-15/FGFR regulates the non-cell-autonomous DDR that is mediated via FGF-like signaling. Using hair follicle stem cells as a paradigm, we demonstrate that the eIF4E2-mediated niche cell regulation of the p53 response in stem cells is highly conserved in mammals. We thus reveal that the somatic niche regulates the CEP-1/p53-mediated DNA damage checkpoint in PGCs. Our data suggest that the somatic niche impacts the stability of heritable genomes.
原始生殖细胞（PGC）中的基因组完整性是生育和物种维持的前提。在秀丽隐杆线虫中，PGC 需要全局基因组核苷酸切除修复（GG-NER）来清除 UV 诱导的 DNA 损伤。如果不能清除这些损伤，就会导致线虫 p53、CEP-1 的激活，从而导致 PGC 的有丝分裂停滞。我们发现，体生殖腺前体细胞（SGP）龛细胞中的 eIF4E2 翻译起始因子 IFE-4 调节 PGC 中的 CEP-1/p53 介导的 DNA 损伤反应（DDR）。我们确定，IFE-4 的翻译靶标 EGL-15/FGFR 调节非细胞自主 DDR，该 DDR 通过 FGF 样信号传递。我们利用毛囊干细胞作为范例，证明了 eIF4E2 介导的龛细胞对干细胞中 p53 反应的调控在哺乳动物中高度保守。因此，我们揭示了体龛细胞调节 PGC 中 CEP-1/p53 介导的 DNA 损伤检查点。我们的数据表明，体龛会影响可遗传基因组的稳定性。
