Paluri Sesha L, Burak Matthew, Senejani Alireza G, Levinson Madison, Rahim Tania, Clairmont Kaylyn, Kashgarian Michael, Alvarado-Cruz Isabel, Meas Rithy, Cardó-Vila Marina, Zeiss Caroline, Maher Stephen, Bothwell Alfred L M, Coskun Erdem, Kant Melis, Jaruga Pawel, Dizdaroglu Miral, Stephen Lloyd R, Sweasy Joann B
Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824, United States.
MassBiologics, Mattapan, MA, 02126, United States.
DNA Repair (Amst). 2021 Sep;105:103152. doi: 10.1016/j.dnarep.2021.103152. Epub 2021 Jun 24.
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 and Polb 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 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（Polβ），一种在碱基切除修复（BER）和微同源性介导的末端连接中起作用的DNA聚合酶。Polβ-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和Polb小鼠会患上狼疮。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，Polβ-Y265C蛋白的低催化活性导致BER中间体的积累，进而导致细胞死亡。我们小鼠中死亡细胞释放的碎片可能会推动狼疮的发展。我们假设，在BER过程中作用于Polβ上游的Neil1和Ogg1 DNA糖基化酶的缺失将导致BER中间体的积累减少，从而使狼疮病情减轻。我们发现，缺失Ogg1和Neil1 DNA糖基化酶的Polb小鼠血清中存在高水平的抗核抗体。然而，这些小鼠患的肾病明显较轻，很可能是由于它们血清中高水平的IgM所致。
