A COMMON MUTATIONAL PATTERN IN COCKAYNE-SYNDROME PATIENTS FROM XERODERMA-PIGMENTOSUM GROUP-G - IMPLICATIONS FOR A 2ND XPG FUNCTION

Xeroderma pigmentosum (XP) patients have defects in nucleotide excisio n repair (NER), the versatile repair pathway that removes UV-induced d amage 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 acti ve genes, a process known as transcription-coupled repair, These two d isorders are usually clinically and genetically distinct, but compleme ntation analyses have assigned a few CS patients to the rare XP groups B, D, or G, The XPG gene encodes a structure-specific endonuclease th at nicks damaged DNA 3' to the lesion during NER, Here we show that th ree XPG/CS patients had mutations that would produce severely truncate d XPG proteins, In contrast, two sibling XPG patients without CS are a ble to make full-length XPG, but with a missense mutation that inactiv ates 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 clini cal phenotype.