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DNA glycosylase deficiency leads to decreased severity of lupus in the Polb-Y265C mouse model

Published

Author(s)

Sesha Paluri, Matthew Burak, Alireza Senenjani, Kelly Carufe, Kaylin Clairmont, Isabel Alvarado-Cruz, Rithy Meas, Michael Kashgarian, Caroline Zeiss, Stephen Maher, Alfred Bothwell, Erdem Coskun, Melis Kant, Pawel Jaruga, Miral M. Dizdar, R S. Lloyd, Joann B. Sweasy

Abstract

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 PolbY265C/+ and PolbY265C/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 PolbY265C/+ 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.
Citation
Dna Repair

Keywords

Systemic Lupus Erythematosus, BER, DNA Polymerase ?-Y265C, Mice Model, OGG1, NEIL1

Citation

Paluri, S. , Burak, M. , Senenjani, A. , Carufe, K. , Clairmont, K. , Alvarado-Cruz, I. , Meas, R. , Kashgarian, M. , Zeiss, C. , Maher, S. , Bothwell, A. , Coskun, E. , Kant, M. , Jaruga, P. , Dizdar, M. , Lloyd, R. and Sweasy, J. (2021), DNA glycosylase deficiency leads to decreased severity of lupus in the Polb-Y265C mouse model, Dna Repair, [online], https://doi.org/10.1016/j.dnarep.2021.103152, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=930645 (Accessed October 27, 2021)
Created June 24, 2021, Updated October 14, 2021