title: A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function.
abstract: Xeroderma pigmentosum (XP) patients have defects in nucleotide excision repair (NER), the versatile repair pathway that removes UV-induced damage and other bulky DNA adducts. Patients with Cockayne syndrome (CS), another rare sun-sensitive disorder, are specifically defective in the preferential removal of damage from the transcribed strand of active genes, a process known as transcription-coupled repair. These two disorders are usually clinically and genetically distinct, but complementation analyses have assigned a few CS patients to the rare XP groups B, D, or G. The XPG gene encodes a structure-specific endonuclease that nicks damaged DNA 3' to the lesion during NER. Here we show that three XPG/CS patients had mutations that would produce severely truncated XPG proteins. In contrast, two sibling XPG patients without CS are able to make full-length XPG, but with a missense mutation that inactivates its function in NER. These results suggest that XPG/CS mutations abolish interactions required for a second important XPG function and that it is the loss of this second function that leads to the CS clinical phenotype.
authors.affiliation: Department of Genetics and Microbiology, University Medical Centre (CMU), Geneva 4, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Nouspikel
authors.forename: P
authors.initials: P
authors.lastname: Lalle
authors.forename: S A
authors.initials: SA
authors.lastname: Leadon
authors.forename: P K
authors.initials: PK
authors.lastname: Cooper
authors.forename: S G
authors.initials: SG
authors.lastname: Clarkson
mesh_terms: D002478:Cells, Cultured; D002648:Child; D003057:Cockayne Syndrome / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D014157:Transcription Factors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5