Mutation of POLB Causes Lupus in Mice

Abstract

Summary A replication study of a previous genome-wide association study (GWAS) suggested that a single nucleotide polymorphism (SNP) linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased POLB expression (Pol β). To determine if decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. Pol β is a key enzyme in the base excision repair (BER) pathway.. We show that mice expressing this hypomorphic POLB allele develop autoimmune pathology strongly resembling SLE. Of note, the immunoglobulin heavy chain junctions from the POL BY265C/C mice have shorter lengths, 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.

Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation

“…The lack of effect of Pol β likely results from the very low APE1 expression in GC B cells, as opposed to our previous interpretation that the BER pathway does not contribute to SSBs needed for A:T mutations (33). By contrast, it has recently been shown that mice expressing a mutant Pol β with very slow polymerization kinetics have increased SHM of the J H4 flank in GC B cells, with the largest effect on transversions at C:G bp (46). Because Pol β interacts with APE1 and XRCC1 during repair of AP sites (31,47), this mutant Pol β might reduce the turnover of APE1, further decreasing the effective APE1 levels and allowing increased access of APE2 to AP sites.…”

Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice

“…In fact, healthy centenarians have lower serum levels of inflammatory cytokines (Ferrucci et al ., 1999), and proinflammatory molecules such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) are upregulated in the aged liver (Rikans et al ., 1999). However, SRT1720, an anti-aging SIRT1 activator, suppresses proinflammatory gene expressions in the livers of aged mice fed a standard diet (Mitchell et al ., 2014) as well as a high-fat diet (Minor et al ., 2011). Although the precise mechanism of age-related inflammation remains elusive, it is important to inhibit inflammation to prevent liver aging.…”

“…Thus, it would be beneficial to identify effective CR mimetics. Resveratrol (Baur et al ., 2006) and SRT1720 (Mitchell et al ., 2014), SIRT1 activators, and rapamycin (Harrison et al ., 2009), a mammalian target of rapamycin (mTOR) inhibitor, have been proposed as candidate CR mimetics. Resveratrol improves survival and decreases age-related changes such as insulin resistance, mitochondrial number, the motor dysfunction, and liver pathology in mice fed a high-calorie diet (Baur et al ., 2006).…”

“…Resveratrol also reduced hepatic steatosis, the levels of reactive oxygen species, and inflammation in high-fat-diet-induced obese mice (Jeon et al ., 2012). SRT1720 extends lifespan, delays onset of age-related metabolic disease, and improves general health in male mice (Mitchell et al ., 2014). Rapamycin was shown to extend the lifespan of mice fed a standard diet (Harrison et al ., 2009; Miller et al ., 2011), but it has been reported to induce hyperlipidemia and glucose intolerance (Houde et al ., 2010).…”

Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity

“…Autoantibodies have been associated with alterations in somatic hypermutation (SHM), which is mediated by activation-induced cytidine deaminase (AID, encoded by Aicda) expressed in GC B cells (56,57). Moreover, knockin mice carrying a hypomorphic mutation in the BER DNA polymerase β (Pol β) have a dramatically increased frequency of SHM and develop autoimmunity and lupus-like disease (58). As altered AID activity can result in apoptosis of GC B cells, we determined whether loss of NEIL3 affects Aicda expression and the frequency of SHM.…”