Xpg

The XPG nuclease cleaves the DNA on the 3' side of the damage; it also has a role in the repair of oxidative damage. Patients from the XP-G complementation group with heterogeneous clinical features are quite rare. Using sequence analysis, Nouspikel et al. have shown that patients who bear missense mutations in the XPG gene have a milder phenotype than those with mutations resulting in truncated forms of the protein (103). The latter usually develop severe combined characteristics of both XP and CS.

Analysis of the XPG gene has revealed that its product is a member of the FEN-1 family of structure-specific endonucleases. Members of this family incise always with the same polarity at junctions of duplex and single-stranded DNA (ss-DNA). XPG cleaves a variety of artificial DNA substrates, and it is required for the incision at the 3' side of the open complex during NER (104,105). Positioning of the XPG protein specifically on the damaged strand seems to be coordinated upon its interaction with TFIIH and possibly RPA, whereas its nuclease activity in NER is dependent on functional XPA protein (48,62,63).

Several lines of evidence indicate that XPG has a second role in the cell, and that this might be an involvement in the repair of oxidative damage. Cells from XP-G/CS patients are deficient in the transcription-coupled repair of thymine glycols, whereas cells from patients that exhibit only XP characteristics are normal (106). This is consistent with the idea that mutations that result in severely truncated forms of XPG protein abolish all of its functions and are responsible for the severe clinical picture observed in XP-G/CS patients. In contrast, missense mutations in the XPG gene result in loss of the nuclease activity but retention of its function in TCR of oxidative damage. This could lead to the milder picture of XP-G patients. Further insight into a possible role for XPG in repair of oxidative damage has come from the finding that XPG stimulates the binding of the hNth1 protein to DNA and increases its activity. hNth1 is a glycosy-lase/AP lyase, which removes thymine glycol and related lesions from DNA (107,108). The stimulatory activity of XPG is retained in mutants inactive in NER (108).

The viability of Xpg knockout mice suggests that XPG is not essential for life. However, these mice are extremely sick, with severe growth retardation and early death by 23 days postpartum (109). The greater severity of the features of Xpg compared with Xpa mice, even though both are completely defective in NER, is consistent with a role for XPG in addition to its involvement in NER.

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