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.
Keywords: AATF; DNA damage; DNA repair; R loop; ciliopathy; nephronophthisis; primary cilia.
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