TY - JOUR
T1 - DNA glycosylase deficiency leads to decreased severity of lupus in the Polb-Y265C mouse model
AU - Paluri, Sesha L.
AU - Burak, Matthew
AU - Senejani, Alireza G.
AU - Levinson, Madison
AU - Rahim, Tania
AU - Clairmont, Kaylyn
AU - Kashgarian, Michael
AU - Alvarado-Cruz, Isabel
AU - Meas, Rithy
AU - Cardó-Vila, Marina
AU - Zeiss, Caroline
AU - Maher, Stephen
AU - Bothwell, Alfred L.M.
AU - Coskun, Erdem
AU - Kant, Melis
AU - Jaruga, Pawel
AU - Dizdaroglu, Miral
AU - Stephen Lloyd, R.
AU - Sweasy, Joann B.
N1 - Publisher Copyright: © 2021 Elsevier B.V.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Base excision repair
KW - DNA glycosylase
KW - DNA polymerase beta
KW - Oxidative DNA damage
KW - Systemic lupus erythematosus
UR - http://www.scopus.com/inward/record.url?scp=85109559567&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109559567&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2021.103152
DO - 10.1016/j.dnarep.2021.103152
M3 - Article
C2 - 34186496
SN - 1568-7864
VL - 105
JO - DNA Repair
JF - DNA Repair
M1 - 103152
ER -