Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany.
Kidney Int. 2019 Apr;95(4):846-858. doi: 10.1016/j.kint.2018.10.034. Epub 2019 Feb 13.
Recent human genetic studies have suggested an intriguing link between ciliary signaling defects and altered DNA damage responses in nephronophthisis (NPH) and related ciliopathies. However, the molecular mechanism and the role of altered DNA damage response in kidney degeneration and fibrosis have remained elusive. We recently identified the kinase-regulated DNA damage response target Apoptosis Antagonizing Transcription Factor (AATF) as a master regulator of the p53 response. Here, we characterized the phenotype of mice with genetic deletion of Aatf in tubular epithelial cells. Mice were born without an overt phenotype, but gradually developed progressive kidney disease. Histology was notable for severe tubular atrophy and interstitial fibrosis as well as cysts at the corticomedullary junction, hallmarks of human nephronophthisis. Aatf deficiency caused ciliary defects as well as an accumulation of DNA double strand breaks. In addition to its role as a p53 effector, we found that AATF suppressed RNA:DNA hybrid (R loop) formation, a known cause of DNA double strand breaks, and enabled DNA double strand break repair in vitro. Genome-wide transcriptomic analysis of Aatf deficient tubular epithelial cells revealed several deregulated pathways that could contribute to the nephronophthisis phenotype, including alterations in the inflammatory response and anion transport. These results suggest that AATF is a regulator of primary cilia and a modulator of the DNA damage response, connecting two pathogenetic mechanisms in nephronophthisis and related ciliopathies.
最近的人类遗传学研究表明，纤毛信号缺陷与肾单位发生病变（NPH）和相关纤毛病中的 DNA 损伤反应改变之间存在有趣的联系。然而，改变的 DNA 损伤反应在肾脏退化和纤维化中的分子机制和作用仍然难以捉摸。我们最近发现，激酶调节的 DNA 损伤反应靶标凋亡拮抗转录因子（AATF）是 p53 反应的主要调节剂。在这里，我们对肾小管上皮细胞中 Aatf 基因缺失的小鼠表型进行了表征。这些小鼠出生时没有明显的表型，但逐渐发展为进行性肾病。组织学表现为严重的肾小管萎缩和间质纤维化，以及皮质髓质交界处的囊肿，这些都是人类肾单位发生病变的特征。Aatf 缺失导致纤毛缺陷和 DNA 双链断裂的积累。除了作为 p53 效应物的作用外，我们还发现 AATF 抑制了 RNA:DNA 杂交（R 环）的形成，这是 DNA 双链断裂的已知原因，并能在体外进行 DNA 双链断裂修复。Aatf 缺陷的肾小管上皮细胞的全基因组转录组分析揭示了几个可能导致肾单位发生病变表型的失调途径，包括炎症反应和阴离子转运的改变。这些结果表明，AATF 是初级纤毛的调节剂和 DNA 损伤反应的调节剂，将纤毛病和相关纤毛病中的两种致病机制联系起来。
