Somatic missense mutations in ERCC2, a key NER gene that encodes the DNA helicase XPD, are present in approximately 10% of muscle-invasive bladder tumors ( 4). Recently, sequencing and functional studies have revealed that NER pathway deficiency is present in a subset of tumors. Following lesion recognition, TC-NER and GG-NER converge on a common NER pathway that excises and replaces the damaged DNA strand in an error-free manner. NER is initiated through two separate branches of lesion recognition: transcription-coupled repair (TC-NER) is activated by RNA polymerase stalling at lesions in transcribed regions, while global genome repair (GG-NER) is able to recognize lesions throughout the genome. Nucleotide excision repair (NER) is a highly conserved DNA repair pathway that recognizes and repairs bulky intrastrand DNA adducts formed by genotoxic agents, such as UV radiation and platinum chemotherapies ( 3). A successful example stemming from this principle is the development of PARP inhibitors for treatment of tumors with homologous recombination (HR) repair deficiency ( 1, 2). Because DNA repair pathway aberrations are common in tumor cells, but are largely absent in normal cells, agents that target DNA repair–deficient cells may have a clinically exploitable therapeutic window. Therapeutic approaches based on the principle of synthetic lethality are an attractive strategy for cancer treatment.
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