Platinum Resistance Related to a Functional NER Pathway

Abstract

Tobacco carcinogens induce DNA adducts that are repaired by the nucleotide excision repair (NER) pathway.1 Inhaled combustion-derived particles, such as cigarette smoke, cause a local pulmonary inflammatory response that is characterized by the influx of neutrophils into the airways. On entering the lung, neutrophils are activated and release reactive oxygen species and an array of proteins, such as myeloperoxidase. A significant reduction of NER in human alveolar epithelial cells was observed when they were cocultured with activated neutrophils.2 NER, a highly versatile pathway for DNA damage removal, is often dysfunctional in non-small cell lung cancer (NSCLC) and could, therefore, be the Achilles heel for customizing chemotherapy. NER removes numerous types of DNA helix-distorting lesions, including cisplatinand ultraviolet-induced photo products.1 Inherited defects in the NER process cause serious repair disorders: xeroderma pigmentosum (XP), with extreme risk of ultraviolet-induced skin cancer, and Cockayne syndrome. NER functions by a “cutand-paste” mechanism in which cisplatin damage recognition, local opening of the DNA helix around the lesion, damage excision, and gap filling occur in successive steps1,3–5 (Figure 1). NER is composed of two subpathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER), which share the same core mechanism but differ in the way lesions are recognized.6 NER-defective XP is classified into seven complementation groups, XPA to XPG. XPC and XPE are specifically defective in GG-NER, which repairs the damage on the nontranscribed strand, whereas the other XP groups involve deficiencies in both TC-NER and GG-NER.7 The first step in GG-NER is damage recognition by the heterodimer XPC/hHR23B, which binds with higher affinity to helix-distorting DNA lesions than to nondamaged, doublestranded DNA1 (Figure 1A). Various NER factors, including transcription factor IIH (TFIIH, a general transcription factor for RNA polymerase II), XPA, replication protein A (RPA), and XPG work together to repair DNA damage (Figure 1B). TFIIH can be divided into two subcomplexes: the core TFIIH (composed of XPB, p62, p52, p44, p34, and p8) and a cdk-activating kinase subcomplex (containing cdk7, cyclin H, and MAT1).7 Both subcomplexes are bridged by XPD. In NER, TFIIH unwinds the duplex DNA around the lesion to allow the recruitment of the NER factors XPA, RPA, XPG, and excision repair cross-complementing 1 (ERCC1)/XPF (Figure 1B). TFIIH, with the two helicases XPB and XPD, opens an approximately 30-base-long DNA segment around the platinum damage. This open intermediate is stabilized by RPA and XPA (Figure 1C). The DNA strand that contains the damaged base(s) is excised by the two NER endonucleases XPG and ERCC1/XPF (Figure 1D). XPG cleaves the damaged DNA strand 3= from the lesion, and ERCC1/XPF cleaves the damaged strand 5= from the lesion (Figure 1D). The resulting gap is filled by DNA polymerase or in the presence of replication factors8 (Figure 1E). Importantly, the ERCC1/XPF structure-specific nuclease has an additional role in the repair of cisplatin adducts besides its function in NER: the recombination repair of interstrand cross-links.9 Moreover, colocalization of ERCC1 foci and RAD51 foci in response to cisplatin treatment has recently been found and may represent recruitment of ERCC1/XPF to sites of recombination repair.10 Nevertheless, in addition to NER, cisplatininduced cytotoxicity requires the interaction of components from several different DNA damage-processing systems.11