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

Paluri, Sesha Lakshmi Arathi; Burak, M.J.; Senejani, Alireza G.; Levinson, Madison; Rahim, Tania; Clairmont, Kaylyn; Kashgarian, Michael; Alvarado-Cruz, Isabel; Meas, Rithy; Cardó-Vila, Marina; Zeiss, Caroline J.; Maher, Stephen E.; Bothwell, Alfred L.M.; Coşkun, Erdem; Kant, Melis; Dizdaroğlu, Miral; Lloyd, R. Stephen; Sweasy, Joann B.

doi:10.1016/j.dnarep.2021.103152

Cited by 5 publications

(5 citation statements)

References 43 publications

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“… 25 Mutations in the POLB genes have been associated with SLE and replicated in independent genome-wide association studies, 26 while POLB defective function has been shown to cause lupus in murine models, 27 also correlating with severe glomerulonephritis. 28 In line with these previous findings, the POLB-Dependent Long Patch Base Excision Repair Reactome pathway was found in our sample to be defective in patients with renal involvement. Defective DNA repair has also been linked to loss of T cell tolerance, predisposing individuals to rheumatoid arthritis.…”

Section: Discussionsupporting

confidence: 92%

“…Interestingly, defective DNA repair mechanisms were here found to be associated with renal activity, corroborating previous literature 25. Mutations in the POLB genes have been associated with SLE and replicated in independent genome-wide association studies,26 while POLB defective function has been shown to cause lupus in murine models,27 also correlating with severe glomerulonephritis 28. In line with these previous findings, the POLB-Dependent Long Patch Base Excision Repair Reactome pathway was found in our sample to be defective in patients with renal involvement.…”

Section: Discussionsupporting

confidence: 88%

“…Mutations in POLB associated with SLE; 26 defective POLB caused nephritis 27 and correlated with severe glomerulonephritis in murine lupus. 28 RNA metabolism tRNA processing and post-transcriptional modification of mRNA metabolism of non-coding mRNA associated with LLDAS/DORIS remission.…”

Section: Discussionmentioning

confidence: 99%

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Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Parodis,

Lindblom,

Barturen

et al. 2024

Annals of the Rheumatic Diseases

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ObjectivesTo unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE).MethodsWe determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission.ResultsWe analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway.ConclusionsWe demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

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Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Parodis,

Lindblom,

Barturen

et al. 2024

Annals of the Rheumatic Diseases

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“…Further analysis documented that the Polb Y265C mouse (hybrid 129/Sv/C57BL/6 background) shows an increase in symptoms associate with systemic lupus erythematosus (Senejani et al, 2014). Consistent with the role of this Polβ mutant as part of the BER pathway, the severity of the lupus symptoms observed in the Polb Y265C KI mouse is diminished after KO of the upstream BER initiating enzymes Ogg1 and Neil1 (Paluri et al, 2021). Interestingly, the autoimmune phenotype exhibited by the Polb Y265C mouse model only requires implantation of the bone marrow isolated from the Polb Y265C KI mouse, suggesting a role for the hematopoietic compartment in disease onset due to the Polβ mutation (Rahim et al, 2022).…”

Section: Gene Knock‐in Mouse Models For Polβmentioning

confidence: 61%

Mouse models to explore the biological and organismic role of DNA polymerase beta

Sobol

2024

Environ and Mol Mutagen

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Gene knock‐out (KO) mouse models for DNA polymerase beta (Polβ) revealed that loss of Polβ leads to neonatal lethality, highlighting the critical organismic role for this DNA polymerase. While biochemical analysis and gene KO cell lines have confirmed its biochemical role in base excision repair and in TET‐mediated demethylation, more long‐lived mouse models continue to be developed to further define its organismic role. The Polb‐KO mouse was the first of the Cre‐mediated tissue‐specific KO mouse models. This technology was exploited to investigate roles for Polβ in V(D)J recombination (variable‐diversity‐joining rearrangement), DNA demethylation, gene complementation, SPO11‐induced DNA double‐strand break repair, germ cell genome stability, as well as neuronal differentiation, susceptibility to genotoxin‐induced DNA damage, and cancer onset. The revolution in knock‐in (KI) mouse models was made possible by CRISPR/cas9‐mediated gene editing directly in C57BL/6 zygotes. This technology has helped identify phenotypes associated with germline or somatic mutants of Polβ. Such KI mouse models have helped uncover the importance of key Polβ active site residues or specific Polβ enzyme activities, such as the PolbY265C mouse that develops lupus symptoms. More recently, we have used this KI technology to mutate the Polb gene with two codon changes, yielding the PolbL301R/V303R mouse. In this KI mouse model, the expressed Polβ protein cannot bind to its obligate heterodimer partner, Xrcc1. Although the expressed mutant Polβ protein is proteolytically unstable and defective in recruitment to sites of DNA damage, the homozygous PolbL301R/V303R mouse is viable and fertile, yet small in stature. We expect that this and additional targeted mouse models under development are poised to reveal new biological and organismic roles for Polβ.

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“…Further analysis documented that the Polb Y265C mouse shows an increase in symptoms associate with systemic lupus erythematosus (SLE) (Senejani et al 2014). Consistent with the role for this Polβ mutant as part of the BER pathway, the severity of the lupus symptoms observed in the Polb Y265C KI mouse is diminished after KO of the upstream BER initiating enzymes Ogg1 and Neil1 (Paluri et al 2021). Interestingly, the autoimmune phenotype exhibited by thePolb Y265C mouse model only requires implantation of the bone marrow isolated from thePolb Y265C KI mouse, suggesting a role for the hematopoietic compartment in disease onset due to the Polβ mutation (Rahim et al 2022).…”

Section: γενε κνοςκ-ιν (κι) μουσε μοδελς φορ πολβmentioning

confidence: 74%

Mouse models to explore the biological and organismic role of DNA polymerase beta

Sobol

2024

Preprint

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

Cited by 5 publications

References 43 publications

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Mouse models to explore the biological and organismic role of DNA polymerase beta

Mouse models to explore the biological and organismic role of DNA polymerase beta

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