Universität zu Köln

Jain, Manaswita ORCID: 0000-0002-5107-7505, Kaiser, Rainer W. J., Bohl, Katrin, Hoehne, Martin, Goebel, Heike, Bartram, Malte P., Habbig, Sandra, Mueller, Roman-Ulrich, Fogo, Agnes B., Benzing, Thomas, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Hoepker, Katja and Slaats, Gisela G. (2019). Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis. Kidney Int., 95 (4). S. 846 - 859. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1755

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jain, Manaswita UNSPECIFIED orcid.org/0000-0002-5107-7505 UNSPECIFIED Kaiser, Rainer W. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohl, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Goebel, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Habbig, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Roman-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Fogo, Agnes B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Hoepker, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Slaats, Gisela G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-152949
DOI:	10.1016/j.kint.2018.10.034
Journal or Publication Title:	Kidney Int.
Volume:	95
Number:	4
Page Range:	S. 846 - 859
Date:	2019
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1523-1755
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RENAL CILIOPATHIES; P53 TRANSCRIPTION; CHE-1 PROTEIN; R-LOOPS; REPLICATION; GROWTH; REPAIR; POLY(ADP-RIBOSYL)ATION; PHOSPHORYLATION; PARTNER Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15294