DNA Polymerase beta, Lupus Erythematosus, Systemic
Systemic lupus erythematosus
Biology | Ecology and Evolutionary Biology
A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLβ gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLβ that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLβ allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.
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Senejani, Ali; Liu, Yanfeng; Kidane, Dawit; Maher, Stephen E.; Zeiss, Caroline J.; Park, Hong-Jae; Kashgarian, Michael; McNiff, Jennifer Madison; Zelterman, Daniel; Bothwell, Alfred L.M.; and Sweasy, Joann B., "Mutation of A DNA Repair Enzyme Causes Lupus in Mice" (2014). Biology and Environmental Science Faculty Publications. 45.
Senejani A.G., Liu Y., Kidane D., Maher S.E., Zeiss C.J., Park H., Kashgarian M., McNiff J.M., Zelterman D., Bothwell A., Sweasy J.B. “Mutation of A DNA Repair Enzyme Causes Lupus in Mice” Cell reports (CELL PRESS) 2014 Jan 16;6(1):1-8. doi:10.1016/j.celrep.2013.12.017.