Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen 2200, Denmark.
Histopathology Core Unit, Spanish National Cancer Research Centre, Madrid 28029, Spain.
Cell Rep. 2018 Sep 18;24(12):3274-3284. doi: 10.1016/j.celrep.2018.08.071.
PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability during embryonic development due to a global accumulation of DNA damage. However, despite the presence of chromosomal instability, extensive p53 activation, and increased apoptosis throughout the embryo, Pich KO embryos survive until day 12.5 of embryonic development. The absence of p53 failed to improve the viability of the Pich KO embryos, suggesting that the observed developmental defects are not solely due to p53-induced apoptosis. Moreover, Pich-deficient mouse embryonic fibroblasts exhibit chromosomal instability and are resistant to RAS/E1A-induced transformation. Overall, our data indicate that PICH is essential to preserve chromosomal integrity in rapidly proliferating cells and is therefore critical during embryonic development and tumorigenesis.
PICH 是一种 DNA 转位酶，对于解决超细线期 DNA 桥和确保染色体分离的保真度至关重要。在这里，我们报告了一种 PICH 缺陷的动物模型的生成，这使我们能够研究其生理相关性。由于 DNA 损伤的全面积累，Pich KO 小鼠在胚胎发育过程中丧失了生存能力。然而，尽管存在染色体不稳定性、广泛的 p53 激活和整个胚胎中增加的细胞凋亡，Pich KO 胚胎仍能存活到胚胎发育的第 12.5 天。缺乏 p53 未能提高 Pich KO 胚胎的存活率，这表明观察到的发育缺陷不仅仅是由于 p53 诱导的细胞凋亡所致。此外，缺乏 PICH 的小鼠胚胎成纤维细胞表现出染色体不稳定性，并对 RAS/E1A 诱导的转化具有抗性。总的来说，我们的数据表明 PICH 对于保持快速增殖细胞中的染色体完整性是必不可少的，因此在胚胎发育和肿瘤发生过程中是至关重要的。
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