Abstract
The nucleotide excision repair (NER) pathway is activated in response to a broad spectrum of DNA lesions, including bulky lesions induced by platinum-based chemotherapeutic agents. Expression levels of NER factors and resistance to chemotherapy has been examined with some suggestion that NER plays a role in tumour resistance; however, there is a great degree of variability in these studies. Nevertheless, recent clinical studies have suggested Xeroderma Pigmentosum group A (XPA) protein, a key regulator of the NER pathway that is essential for the repair of DNA damage induced by platinum-based chemotherapeutics, as a potential prognostic and predictive biomarker for response to treatment. XPA functions in damage verification step in NER, as well as a molecular scaffold to assemble other NER core factors around the DNA damage site, mediated by protein–protein interactions. In this review, we focus on the interacting partners and mechanisms of regulation of the XPA protein. We summarize clinical oncology data related to this DNA repair factor, particularly its relationship with treatment outcome, and examine the potential of XPA as a target for small molecule inhibitors.
Highlights
Introduction and Nucleotide Excision RepairNucleotide excision repair (NER) is a universal and versatile repair pathway capable of removing a broad spectrum of DNA helix-distorting lesions, such as bulky DNA adducts
It is tempting to speculate that low HIF-1α levels resulting in low Xeroderma Pigmentosum group A (XPA) levels may lead to reduced repair of CDDP-induced DNA damage in testicular germ cell tumours (TGCTs), which could explain the innate CDDP susceptibility of this tumour type [112]
Three further single nucleotide polymorphism (SNP) reside in intron sequences of XPA: rs3176658, which causes C to T transition, rs3176721, a C to A transversion, and rs2808667, a T to C transition. rs3176658 and rs3176721 are associated with efficacy of platinum-based chemotherapy in lung cancer (LC) [188], while rs3176658 alone has been shown to be significantly associated with LC risk [189] and with response to neoadjuvant radiochemotherapy treatment of locally advanced rectal cancer (RC) [190]
Summary
Nucleotide excision repair (NER) is a universal and versatile repair pathway capable of removing a broad spectrum of DNA helix-distorting lesions, such as bulky DNA adducts. On damaged DNA, XPC-HR23B resides at the lesion site long enough to form the open complex, while this is not the case on undamaged DNA [9,10] Another damage sensor in GG-NER is the damaged DNA binding (DDB) complex, consisting of the DDB1 and DDB2 ( known as Xeroderma Pigmentosum group E protein) subunits. TFIIH is a large protein complex that consists of 10 different subunits It is functionally organized into a core and a CDK-activating kinase (CAK) sub-complex. XPA interacts both with TFIIH and XPC-HR23B and stabilizes the opened bubble together with the ssDNA binding protein (RPA) [6,24]. XPA functions in conjunction with RPA as the scaffold for the assembly and stabilization of the NER pre-incision complex, organizing the damaged DNA and this complex to ensure lesions are appropriately excised. Understanding the biological function of these interactions depends on the availability of structural information for these complexes
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