FIGURE 2.

Recent insights in the pathophysiology of karyomegalic interstitial nephritis. Tubular epithelial cells are exposed to various types of aggressions, potentially leading to cellular injury. In case of DNA damage with ICL, which may be favored by environmental genotoxins, FANCM is recruited at the site of ICL and initiates the recruitment of the Fanconi anemia core complex leading to the monoubiquitylation of FANCD2 and FANCI, and cell cycle blockade to allow DNA repair. FAN1 is then recruited by monoubiquitinated FANCD2 and cleaves DNA successively, allowing to excise an interstrand crosslink from 1 strand through flanking incisions. FAN1 has been reported to be more specifically involved in the repair of ICL-induced DNA breaks by being required for efficient homologous recombination, and probably acts in the resolution of homologous recombination intermediates. In the absence of FAN1, DNA repair is impaired resulting in the accumulation of DNA damage and impairment of cell proliferation. In particular, FAN1 could be more specifically engaged in the repair of a possible “renal-specific” DNA damage. FAN1 = FANCD2/FANCI-Associated Nuclease 1; FANCI = Fanconi Anemia Complementation group I, FANCD2 = Fanconi Anemia Complementation group D2, FANCM = Fanconi Anemia Complementation group M, ICL = interstrand crosslinks.