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.

FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2

“…Its efficient recruitment to mitomycin C (MMC)-induced DNA damage foci by ub-FANCD2 and the requirement of its UBZ domain in this process strongly implied a link between FAN1 and the FA pathway. However, this prediction was not substantiated by genetic data showing that FAN1 mutations segregate with KIN rather than with FA 10 – 12 . Moreover, FAN1-deficient cells are generally less sensitive to ICL-inducing agents than FA cells and, unlike FA cells, display no growth defects under normoxic conditions 7 .…”

New Familial Cases of Karyomegalic Interstitial Nephritis With Mutations in the FAN1 Gene

“…It is possible that FAN1 may respond to a subset of ICLs that is somehow different in nature from the ICLs dealt with by the FA pathway. This might re ect a difference in the chemical nature of the ICLs or a difference in the genomic context of the ICLs recognized by the two pathways [37].…”

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

“…However, a number of studies suggested that the cross-link repair function of FAN1 is not within the FA pathway as: (i) homologs of FAN1 have been found in bacteria, archaea, and unicellular eukaryotes which lack FA proteins (19,(21)(22)(23), (ii) mutations in FAN1 do not cause FA, but instead a kidney disorder called karyomegalic interstitial nephritis (KIN) (24), (iii) N-terminal UBZ domain is dispensable for ICL repair, but is required for genomic maintenance, suggesting that the interaction of FAN1 with ID serves a function outside of ICL repair (25)(26)(27). Nevertheless, the sensitivity of FAN1-deficient cells to ICL-forming agents implicates FAN1 in ICL resolution independently of the FA pathway.…”