Current model of ICL repair by the FA pathway. (A) When DNA containing an ICL undergoes replication, the leading strands of 2 converging replication forks stop at the lesion. The FA core complex is recruited to chromatin, where it subsequently monoubiquitinates its 2 substrates, FANCD2 and FANCI. (B) Next, the 2 sister chromatids are uncoupled via dual incisions on either side of the ICL, possibly by SLX4-XPF-ERCC1. (C) Subsequently, a translesion DNA polymerase (TLS pol) extends the nascent strand beyond the ICL. (D) Finally, 2 fully repaired DNA duplexes are generated through the action of nucleotide excision repair (NER) on the top duplex and homologous recombination (HR) on the bottom duplex. The remaining FA proteins (FANCD1/BRCA2, FANCO/RAD51C, FANCN/PALB2, and FANCJ/BRIP1) are thought to be involved in these recombination transactions.