Current model of the Fanconi anemia pathway. (A) The FA proteins are depicted in the normal cell nucleus. In response to DNA damage, or during normal S-phase progression, the FANCD2 protein is monoubiquitinated on lysine 561. Efficient monoubiquitination requires several proteins, including ATR, RPA, and an intact FA core complex. Monoubiquitination of FANCD2 targets the protein into nuclear foci and chromatin fraction where it interacts with BRCA2. The function of monoubiquitinated FANCD2 (FANCD2-Ub) in chromatin remains unknown, and it may regulate HR repair, translesion DNA synthesis, or both. USP1 negatively regulates monoubiquitination of FANCD2. (B) This figure depicts several chromatin proteins that appear to interact in the repair of the DNA interstrand crosslink (see “Localization of FA proteins in chromatin”).