Figure 2.

Interstrand crosslinks can be repaired by replication-independent (left) and replication-dependent (right) mechanisms. Both repair pathways involve dual incisions, translesion synthesis across the crosslinked segment, and nucleotide excision repair (NER) to remove the incised crosslink. Replication-dependent interstrand crosslink (ICL) repair also involves homologous recombination (HR). When forks converge on an ICL, BRCA1 and RAD51 protect the stalled fork, and the Fanconi anemia (FA) repair pathway repairs the crosslink. FA repair is initiated by the ubiqutination of FANCD2, which recruits nucleases XPF, MUS81/EME1, and SLX1 to incise the crosslink, followed by translesion synthesis across the lesion, NER to remove the lesion, and HR to repair the replication fork. Both mechanisms are error free, except for mutations that may be introduced by translesion synthesis polymerases. DSB = double-strand break; FA = Fanconi anemia; HR = homologous recombination; ICL = interstrand crosslink; NER = nucleotide excision repair; TC-NER = transcription-coupled NER.