Defective repair of O6-methylguanine-DNA in primary Sjögren's syndrome patients predisposed to lymphoma.
OBJECTIVE
To investigate a role for mutation in the aetiogenesis of autoimmune disease by examining levels of repairing enzyme for the promutagenic DNA base lesion, O6-methylguanine, in lymphocyte extracts from patients with autoimmune diseases. We included primary Sjögrens syndrome (PSS) patients because of the additional relevance of their being at increased risk (> 40-fold) of developing lymphoma.


METHODS
Lymphocytes were prepared from patients with PSS (n = 22) (12 with parotid gland enlargement, an indicator of extensive lymphoproliferation), rheumatoid arthritis (n = 12), primary biliary cirrhosis (n = 11), osteoarthritis (n = 12), and healthy individuals (n = 11). MGMT amounts were determined in lymphocyte extracts by direct enzyme assay and expressed in relation to total extract DNA, protein, or cell number.


RESULTS
We found no defect in the repairing methyltransferase enzyme between any of the groups, except in PSS patients at increased risk of developing lymphoma (those with enlarged parotid glands): p < 0.0001 and p = 0.0056, compared with healthy controls and PSS patients without parotid gland swelling, respectively.


CONCLUSIONS
Our findings implicate persistence of O6-methylguanine-DNA in the aetiology of lymphoma associated with PSS, and raise the possibility that an alternative repair process for O6-methylguanine-DNA, nucleotide excision repair, might be defective in autoimmune disease.
Guo
K
K
Department of Medicine (Medical Molecular Biology Group), Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.
Major
G
G
Foster
H
H
Bassendine
M
M
Collier
J
J
Ross
D
D
Griffiths
I
I
D000368:Aged; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004260:DNA Repair; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives*; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008223:Lymphoma / Q000235:genetics*; D008780:Methyltransferases / Q000097:blood; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012859:Sjogren's Syndrome / Q000150:complications / Q000201:enzymology / Q000235:genetics*
D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase