XPF-ERCC1: Linchpin of DNA crosslink repair

Both Escherichia coli and yeasts almost exclusively rely on a modified form of nucleotide excision repair (NER) [1, 8], a cut-and-paste pathway that is best known for its ability to remove UV-light–induced DNA photodimers (whose defects result in another human syndrome, Xeroderma pigmentosum [XP]). XPF–ERCC1 has received much attention, since it was realised several decades ago that XPF–ERCC1-deficient mammalian cells are exquisitely sensitive to ICL-inducing agents [13, 14], showing a sensitivity that exceeds that observed in other NER-deficient and FA-deficient cells. [...]there is a consensus from cellular and biochemical studies that XPF–ERCC1 is the major activity responsible for making the endonucleolytic DNA incisions that initiate ICL repair [15–17]. [...]a more likely culprit is a yet-to-be identified endogenously generated DNA lesion. [...]CSB, and a transcription-coupled repair pathway outside of NER might be involved, as mice jointly defective for CSB and XPA have a shortened life span and dramatic progeroid features compared to their cognate single disruptants [21, 22]. [...]the FAN1 (Fanconi-associated nuclease 1) nuclease, mismatch repair system, and the SNM1A (sensitive to nitrogen mustard 1A) exonuclease have all been implicated in ICL recognition and processing [24–26] and are candidates for mediating any XPF–ERCC1-dependent pathway, noting