The Polb gene encodes DNA polymerase beta (Pol β), a DNA polymerase that functions in base excision repair (BER) and microhomology-mediated end-joining. The Pol β-Y265C protein exhibits low catalytic activity and fidelity, and is also deficient in microhomology-mediated end-joining. We have previously shown that the Polb^Y265C/+ and Polb^Y265C/C mice develop lupus. These mice exhibit high levels of antinuclear antibodies and severe glomerulonephritis. We also demonstrated that the low catalytic activity of the Pol β-Y265C protein resulted in accumulation of BER intermediates that lead to cell death. Debris released from dying cells in our mice could drive development of lupus. We hypothesized that deletion of the Neil1 and Ogg1 DNA glycosylases that act upstream of Pol β during BER would result in accumulation of fewer BER intermediates, resulting in less severe lupus. We found that high levels of antinuclear antibodies are present in the sera of Polb^Y265C/+ mice deleted of Ogg1 and Neil1 DNA glycosylases. However, these mice develop significantly less severe renal disease, most likely due to high levels of IgM in their sera.

Polb基因编码 DNA 聚合酶 β (Pol β)，这是一种在碱基切除修复 (BER) 和微同源介导的末端连接中起作用的 DNA 聚合酶。Pol β-Y265C 蛋白表现出低催化活性和保真度，并且在微同源性介导的末端连接方面也存在缺陷。我们之前已经表明Polb ^Y265C/+和Polb ^Y265C/C小鼠会发展为狼疮。这些小鼠表现出高水平的抗核抗体和严重的肾小球肾炎。我们还证明了 Pol β-Y265C 蛋白的低催化活性导致 BER 中间体的积累，从而导致细胞死亡。我们小鼠垂死细胞释放的碎片可能会导致狼疮的发展。我们假设删除Neil1和在 BER 期间作用于 Pol β 上游的Ogg1 DNA 糖基化酶会导致更少的 BER 中间体积累，从而导致狼疮的严重程度降低。我们发现在Ogg1和Neil1 DNA 糖基化酶缺失的Polb ^Y265C/+小鼠的血清中存在高水平的抗核抗体。然而，这些小鼠的肾脏疾病严重程度明显降低，这很可能是由于其血清中 IgM 水平高。