XPG: Its Products and Biological Roles

Abstract

Xeroderma pigmetosum patients of the complementation group G are rare. One group of XP-G patients displays a rather mild and typical XP phenotype. Mutations in these patients interfere with the function of XPG in the nucleotide excision repair, where it has a structural role in the assembly of the preincision complex and a catalytic role in making the incision 3' to the damaged site in DNA. Another set of XP-G patient is much more severely affected, displaying combined symptoms of xeroderma pigmentosum and Cockayne syndrome, referred to as XP/CS complex. Although the molecular basis leading to the XP/CS complex has not yet been fully established, current evidence suggests that these patients suffer from a mild defect in transcription in addition to a repair defect. Here, the history of how the XPG gene was discovered, the biochemical properties of the XPG protein, and the molecular defects found in XP-G patients and mouse models are reviewed.

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

“…Ala-818 is in the nuclease I domain and mutation at this site is likely to inactivate nuclease activity of the protein without affecting its overall structure. A similar mutation 26 aa away, p.Ala792Val, also resulted in a mild phenotype in XP124LO and 125LO (39,40).…”

“…The XPG nuclease contains two domains (N and I) required for nuclease activity, separated by a large spacer domain (Fig. 5B), whose function is unclear, although it is required for interaction with transcription factor IIH (TFIIH) (39). Ala-818 is in the nuclease I domain and mutation at this site is likely to inactivate nuclease activity of the protein without affecting its overall structure.…”

Mediator links transcription and DNA repair by facilitating Rad2/XPG recruitment

“…Rad2/XPG, the 39 endonuclease implicated in NER, is one of such factor. Mutations in the human XPG gene give rise to a xeroderma pigmentosum (XP) sometimes associated with Cockayne syndrome (CS) (Clarkson 2003;Scharer 2008). Rad2/XPG, together with the Rad1-Rad10/XPF-ERCC1 59 endonuclease, cleaves the damaged DNA strand in both NER pathways, GGR and TCR, resulting in the release of a DNA fragment containing the DNA lesion.…”

Multiple DNA Binding Domains Mediate the Function of the ERCC1-XPF Protein in Nucleotide Excision Repair

“…It has additional roles in transcription in conjunction with TFIIH (1). The roles of XPG outside of NER are manifest in the severe phenotypes of many XP-G patients (15,16). By contrast, most of the known XP-F patients present with a mild XP phenotype and have significant residual NER activity due to the presence of low levels of active XPF protein (17).…”