title: Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice.
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 (Fan1(nd/nd)) mice develop a mild form of KIN. The karyomegalic nuclei from Fan1(nd/nd) kidneys are polyploid, and fibroblasts from Fan1(nd/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.
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Christophe
authors.initials: C
authors.lastname: Lachaud
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Meghan
authors.initials: M
authors.lastname: Slean
authors.affiliation: School of Veterinary Medicine, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: Department of Head and Neck Pathology, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Lock
authors.affiliation: Department of Head and Neck Pathology, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Edward
authors.initials: E
authors.lastname: Odell
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Dennis
authors.initials: D
authors.lastname: Castor
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Rachel
authors.initials: R
authors.lastname: Toth
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Rouse
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D003851:Deoxyribonucleases / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D055879:Gene Knock-In Techniques; D007668:Kidney / Q000473:pathology; D051379:Mice; D064251:Multifunctional Enzymes; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D011123:Polyploidy
chemical_list: D064251:Multifunctional Enzymes; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C000596972:Fan1 protein, mouse
keywords: FAN1; FANCD2; Fanconi anemia; ICL; KIN; karyomegaly