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

Abstract

In this study, Lachaud et al. investigated the cause of karyomegalic interstitial nephritis (KIN), a form of chronic kidney disease characterized by karyomegaly. They demonstrate that mice lacking Fan1 nuclease activity recapitulate the symptoms of KIN, providing new insights into how Fan1 nuclease activity contributes to the KIN phenotype.

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.