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Your Environment. Your Health.

New Animal Model Reveals Role of Abnormal DNA Repair in Lupus

Joann B. Sweasy, PhD
Yale University
NIEHS Grant R01ES019179

An NIEHS grantee and colleagues discovered that a genetic mutation involved in DNA repair leads to lupus in mice. Their new mouse model of lupus could provide insight into the environmental mechanisms of the disease and, potentially, other autoimmune diseases.

The lack of an animal model has hindered the investigations of systemic lupus erythematosus (SLE), which causes widespread inflammation in internal organs, joints, and the nervous system. Genome-wide association studies have suggested that a mutation in the gene coding for DNA polymerase beta is involved in SLE. DNA polymerase beta is a key enzyme in the genome integrity process of base excision repair, which defends cells and organisms against direct insults to DNA.

To determine if decreased DNA polymerase beta activity results in SLE, the researchers genetically engineered mice to express lower amounts of the enzyme. The mutant mice developed lupus-like disease and shorter antibody heavy-chain junctions. They also showed dramatically increased levels of somatic hypermutation, a process by which the immune system adapts to new foreign elements. The researchers say that their findings suggest that mutations in DNA repair genes associated with immunological processes could lead to the development of autoimmune disease, including SLE.

Citation: Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB. 2014. Mutation of POLB Causes Lupus in Mice. Cell Rep 6(1):1-8.

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