Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
- Christophe Lachaud1,
- Meghan Slean1,
- Francesco Marchesi2,
- Claire Lock3,
- Edward Odell3,
- Dennis Castor1,4,
- Rachel Toth1 and
- John Rouse1
- 1MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
- 2School of Veterinary Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
- 3Department of Head and Neck Pathology, Guy's Hospital, London SE1 9RT, United Kingdom
- Corresponding author: j.rouse{at}dundee.ac.uk
Abstract
The Fan1 endonuclease is required for repair of DNA interstrand cross-links (ICLs). Mutations in human Fan1 cause karyomegalic interstitial nephritis (KIN), but it is unclear whether defective ICL repair is responsible or whether Fan1 nuclease activity is relevant. We show that Fan1 nuclease-defective (Fan1nd/nd) mice develop a mild form of KIN. The karyomegalic nuclei from Fan1nd/nd kidneys are polyploid, and fibroblasts from Fan1nd/nd mice become polyploid upon ICL induction, suggesting that defective ICL repair causes karyomegaly. Thus, Fan1 nuclease activity promotes ICL repair in a manner that controls ploidy, a role that we show is not shared by the Fanconi anemia pathway or the Slx4–Slx1 nuclease also involved in ICL repair.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.276287.115.
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Freely available online through the Genes & Development Open Access option.
- Received December 9, 2015.
- Accepted February 16, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
