DNA glycosylase deficiency leads to decreased severity of lupus in the Polb-Y265C mouse model
| Autor: | Tania Rahim, R. Stephen Lloyd, Joann B. Sweasy, Melis Kant, Alireza G. Senejani, Madison Levinson, Stephen E. Maher, Miral Dizdaroglu, Caroline J. Zeiss, Rithy Meas, Marina Cardó-Vila, Sesha L. A. Paluri, Kaylyn Clairmont, Michael Kashgarian, Isabel Alvarado-Cruz, Pawel Jaruga, Alfred L. M. Bothwell, Erdem Coskun, Matthew J. Burak |
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| Rok vydání: | 2020 |
| Předmět: |
Anti-nuclear antibody
DNA Repair NEIL1 DNA polymerase beta Biology Biochemistry Article DNA Glycosylases 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine medicine Animals Lupus Erythematosus Systemic Molecular Biology Gene Polymerase DNA Polymerase beta 030304 developmental biology 0303 health sciences Systemic lupus erythematosus Cell Biology Base excision repair DNA medicine.disease Molecular biology Disease Models Animal Oxidative Stress chemistry DNA glycosylase 030220 oncology & carcinogenesis Mutation biology.protein Gene Deletion |
| Zdroj: | DNA Repair (Amst) |
| ISSN: | 1568-7856 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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