The Fan1 endonuclease is required for repair of DNAinterstrand 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 fromFan1nd/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.
- Fanconi anemia