Of the eight human genes implicated in
xeroderma pigmentosum, defects in XPG produce some of the most clinically diverse symptoms. These range from mild freckling to severe skeletal and neurologic abnormalities characteristic of
Cockayne syndrome. Mildly affected
xeroderma pigmentosum group G patients have diminished XPG
endonuclease activity in nucleotide excision repair, whereas severely affected
xeroderma pigmentosum group G/
Cockayne syndrome patients produce truncated XPG
proteins that are unable to function in either nucleotide excision repair or the transcription-coupled repair of oxidative lesions. The first two
xeroderma pigmentosum group G patients, XP2BI and XP3BR, were reported before the relationship between
xeroderma pigmentosum group G and
Cockayne syndrome was appreciated. Here we provide evidence that both patients produce truncated
proteins from one XPG allele. From the second allele, XP2BI generates full-length XPG of 1186
amino acids containing a single L858P substitution that has reduced stability and greatly impaired
endonuclease activity. In XP3BR, a single base deletion and alternative splicing at a rare noncanonical AT-AC intron produces a 1185
amino acid protein containing 44 internal non-XPG residues. This
protein is stably expressed but it also has greatly impaired
endonuclease activity. These four XPG products can thus account for the severe ultraviolet sensitivity of XP2BI and XP3BR fibroblasts. These cells, unlike those from
xeroderma pigmentosum group G/
Cockayne syndrome patients, are capable of limited transcription-coupled repair of oxidative lesions. Our results suggest that the L858P
protein in XP2BI and the almost full-length XPG
protein in XP3BR are responsible for this activity and for the absence of severe early onset
Cockayne syndrome symptoms in these patients.