Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice

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-defecti...

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Autores principales: Lachaud, Christophe, Slean, Meghan, Marchesi, Francesco, Lock, Claire, Odell, Edward, Castor, Dennis, Toth, Rachel, Rouse, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Research Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803050/
https://www.ncbi.nlm.nih.gov/pubmed/26980188
http://dx.doi.org/10.1101/gad.276287.115
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author Lachaud, Christophe
Slean, Meghan
Marchesi, Francesco
Lock, Claire
Odell, Edward
Castor, Dennis
Toth, Rachel
Rouse, John
author_facet Lachaud, Christophe
Slean, Meghan
Marchesi, Francesco
Lock, Claire
Odell, Edward
Castor, Dennis
Toth, Rachel
Rouse, John
author_sort Lachaud, Christophe
collection PubMed
description 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.
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spelling pubmed-48030502016-04-11 Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice Lachaud, Christophe Slean, Meghan Marchesi, Francesco Lock, Claire Odell, Edward Castor, Dennis Toth, Rachel Rouse, John Genes Dev Research Communication 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. Cold Spring Harbor Laboratory Press 2016-03-15 /pmc/articles/PMC4803050/ /pubmed/26980188 http://dx.doi.org/10.1101/gad.276287.115 Text en © 2016 Lachaud et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ 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/.
spellingShingle Research Communication
Lachaud, Christophe
Slean, Meghan
Marchesi, Francesco
Lock, Claire
Odell, Edward
Castor, Dennis
Toth, Rachel
Rouse, John
Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title_full Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title_fullStr Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title_full_unstemmed Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title_short Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice
title_sort karyomegalic interstitial nephritis and dna damage-induced polyploidy in fan1 nuclease-defective knock-in mice
topic Research Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803050/
https://www.ncbi.nlm.nih.gov/pubmed/26980188
http://dx.doi.org/10.1101/gad.276287.115
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