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Although various schemes for interstrand crosslink (ICL) repair incorporate DNA recombination, replication, and double-strand break intermediate steps, action of the nucleotide excision repair (NER) system or some variation of it is a common feature of most models. In the bacterium Escherichia coli, the NER enzyme UvrABC can incise on either side of an ICL to unhook the crosslink, and can proceed via a subsequent recombination step. The relevance of NER to ICL repair in mammalian cells has been challenged. Of all NER mutants, it is clear that ERCC1 and XPF-defective cells show the most pronounced sensitivities to ICL-inducing agents, and defects in ICL repair. However, there is good evidence that cells defective in NER proteins including XPA and XPG are also more sensitive than normal to ICL-inducing agents. These results are summarized here, together with evidence for defective crosslink removal in NER-defective cells. Studies of incision at sites of ICL by cell extracts and purified proteins have been done, but these studies are not all consistent with one another and further research is required. Environ. Mol. Mutagen. 51:520-526, 2010.