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.
Highlights
DNA interstrand cross-links (ICLs) are toxic lesions that block the progression of replisomes
To test the importance of the nuclease activity of Fan1 for ICL repair, we introduced a Fan1-inactivating mutation in the mouse genome to make knock-in mice
GENES & DEVELOPMENT 30:639–644 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org the nuclease-dead Fan1 mutant does not act in a dominant-negative manner (Fig. 1A)
Summary
Mutations in human Fan cause karyomegalic interstitial nephritis (KIN), but it is unclear whether defective ICL repair is responsible or whether Fan nuclease activity is relevant. Consistent with the idea that the role of Fan in ICL repair is different from the FA pathway, biallelic mutations in Fan do not cause FA Instead, they cause a form of chronic kidney disease referred to as karyomegalic interstitial nephritis (KIN) (Zhou et al 2012). The cause of the karyomegaly seen in KIN is not understood, and it is not clear whether this or any of the other characteristics of KIN in patients with Fan mutations is caused by defective ICL repair It is not clear whether the nuclease activity of Fan is required to prevent KIN, an issue that we address in this study
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