XPA verifies the DNA damage and positions the excision nucleases. Patients from the XP-A complementation group exhibit the most severe phenotypes with multiple skin cancers and neurological abnormalities (10). XP-A is one of the most common complementation groups, with the highest prevalence in Japan (43). Cells from most XP-A patients have no NER activity, and they are defective in TCR and GGR pathways, suggesting that XP-A plays a central role in NER.

The XPA gene product is a 31-kD metalloprotein that contains a zinc finger motif indicating DNA binding activity (44). There are several reports that show the affinity of XPA for NER-specific DNA lesions, including 6-4 PPs and CPDs (45-47). In addition, XPA interacts with the single-stranded DNA binding protein, RPA, another essential NER protein factor that is also necessary for recombination and replication. Even though XPA has a higher preference for binding damaged over undamaged DNA, this preference increases significantly upon interaction of XPA with RPA (48,49). A short region of 122 amino acids has been identified as the minimal region of XPA required for its DNA-binding activity (50), which is also essential for its function (47,51). Nuclear magnetic resonance (NMR) studies have revealed two subdomains in this region: an N-terminal zinc-binding core and a C-terminal loop-rich subdomain linked together with a short sequence (52-54). Chemical shift perturbation studies have shown that even though the zinc motif is essential for the NER function of XPA, it is the loop-rich subdomain that binds directly to DNA (52-54).

XPA interacts with several of the NER proteins, such as ERCC1 (see Sec. IV.G) (55,56), TFIIH (57,58), CSB protein, and the p34 subunit of the basal transcription factor TFIIE (57,59). Because of this apparent central role of XPA and the severe cellular and clinical phenotype of XP-A patients, it had been accepted dogma for many years that XPA was the factor responsible for damage detection and recruitment of the NER components. However, recent data described above have shown that this is not the case, and that XPC-HR23B is the initial sensor of DNA damage (25,27,60). Using the local UV irradiation technique described above, Volker and coworkers have demonstrated that the assembly of the core NER factors, TFIIH, and XPG depends on the previous binding of the XPC-HR23B protein complex at the site of the damage, but it does not require a functional XPA protein (27). In contrast, recruitment and positioning of the XPF/ERCC1 complex at the 5' side of the UV-induced DNA lesion and the incision activity of XPF/ERCC1 and XPG at the 5' and 3' side of the damage, respectively (see Sec. IV.F and G), are completely dependent on the XPA protein, in cooperation with RPA (61-63). It is likely that RPA binds to the undamaged strand and protects it from cleavage (63). The association of RPA with XPA generates a double-check sensor that detects simultaneously single-stranded regions (RPA) and backbone distortion (XPA) (64). The above findings place XPA in a later step after damage recognition, possibly in the verification of NER specific lesions and in positioning the incision factors correctly around the damage. Since verification of the existing damage is necessary in GGR and TCR, it also explains the deficiency of XP-A cells in both pathways.

Many different mutations have been identified in XP-A patients (65). Most of them are truncating mutations, but several missense mutations also have been detected. XP-A is relatively common in Japan and analysis of the mutations reveals a founder effect, with the majority of mutations being a G to C transition at the acceptor site of intron 3, which results in missplicing and a truncated protein (13).

Two different groups have generated NER-deficient Xpa mice. The mice develop normally, are fertile, and they do not show any enhanced lethality at up to 1.5 years. A small increased incidence of liver carcinomas and lymphomas was detected in older mice, but no spontaneous neurological abnormalities were observed. Xpa mice are extremely sensitive to skin carcinogenesis induced by UVB or dimethylbenzanthracene (66,67). Also, UVB-induced immunosuppression is greatly enhanced (68,69), implying that impairment of the immune system after UV exposure might contribute to the high incidence of skin cancer in XP-A patients (see Sec. V).

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How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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