XPA: DNA Repair Protein of Significant Clinical Importance

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.

Keywords: XPA protein; biomarker; cancer; nucleotide excision repair; prognostic and predictive value; single nucleotide polymorphism; small molecule inhibitors.

Figure 1

XPA domains and interacting partners. Domain structure of the human XPA protein (A). XPA interaction partners involved in NER (B). XPA interaction partners outside NER (C). Only those partners are shown for which the binding sites on XPA have been mapped. Not to scale.

Figure 2

Transcriptional control of the XPA protein level. Transcription factors BMAL1 and CLOCK heterodimerize and drive the transcription of their negative regulators PER and CRY. This negative feedback loop sets up the rhythmic oscillation and drives circadian clocks. The BMAL1/CLOCK heterodimer also regulates the expression of XPA resulting in rhythmic oscillation of the XPA intracellular level and NER efficiency (A). In hypoxia, HIF-1α forms a dimer with HIF-1β. After translocation to nucleus, the HIF-1 heterodimer binds the HRE in promoter region of the XPA gene and upregulates expression of XPA leading to an increased NER efficiency (B). The HMGA1 protein binds to negative regulatory element in promoter region of the XPA gene and represses its transcription (C).

Figure 3

Proposed ATR-SIRT1-XPA and ATR-HERC2-XPA axis. UV-induced DNA damage activates the ATR kinase, which promotes SIRT1 localization at the damage sites and SIRT1-mediated deacetylation of XPA. Deacetylated XPA is a substrate for ATR-mediated phosphorylation. Phosphorylated XPA enhances the repair of damaged DNA (A). Upon UV radiation, ATR facilitates the dissociation of the HERC2-XPA complex and prevents XPA ubiquitination and subsequent degradation (B).