DNA Damage and Deficiencies in the Mechanisms of Its Repair: Implications in the Pathogenesis of Systemic Lupus Erythematosus

Mireles-Canales, Martha Paola; González-Chávez, Susana Aideé; Quiñonez-Flores, Celia María; León-López, Ever Adán; Pacheco‐Tena, César

doi:10.1155/2018/8214379

Cited by 26 publications

(18 citation statements)

References 127 publications

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“…Recent evidence indicates that patients with SLE have higher levels of DNA damage than normal subjects, and that polymorphisms in genes involved in the preservation of the genomic stability increase the risk for SLE (32)(33)(34). Furthermore, experience from animal models reinforces the importance of defective repair in the development of SLElike disease (35), suggesting that therapeutic potential of targeting DNA damage and DNA repair responses in SLE pathogenesis (36,37). Indeed, oxidized DNA has a greater immunostimulatory capacity to stimulate type I IFN than does normal DNA, possibly due to increased resistance to degradation by the 3 ′ repair exonuclease 1 TREX 1 (38).…”

Section: Discussionmentioning

confidence: 99%

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

et al. 2020

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Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2 ′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 −/− mice showed increased influx of Ly6C hi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 −/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 −/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

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Section: Discussionmentioning

confidence: 99%

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

et al. 2020

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“…Indeed, a genetic analysis of chromosome 1q41-q42 revealed that a specific allele of PARP1, with a length of approximately 85bp, confers defective DNA repair and abnormal apoptosis, thus predisposing to SLE [114]. The contribution of polymorphisms in DDR/R components to the development and progression of SLE has been recently reviewed here [115].…”

Section: Gene Polymorphisms Associated With Impaired Dna Repair Machimentioning

confidence: 99%

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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“…The present study's distinguished findings were that the male gender and G/G genotype have 4.6-and 3.5-times higher odds with exhibit anemia, respectively. This may be a manifestation of the enhanced effect of some environmental factors such as exposure to UV as a cofactor for DNA damage repair defects associated with G allele genotype in the Caucasian population, associated with the severity of some autoimmune manifestations [40]. The statistical analysis performing SNP exact test for Hardy-Weinberg equilibrium revealed that the p-value for the control group was 0.49 (Insignificant), which means that the requirement of Hardy-Weinberg equilibrium exists.…”

Section: Discussionmentioning

confidence: 98%

“…Additionally, negative regulation of the genes encoding the proteins involved in the NER pathway in SLE patients, specifically DDB1, ERCC2, XPA, and XPC, has been found [40].…”

Section: Discussionmentioning

confidence: 99%

Gene Polymorphism of XRCC1 in Systemic Lupus Erythematous

Zaki¹,

Abdelsalam²,

Bassiouni³

et al. 2021

TORJ

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Introduction: There are debates about the role of the X-ray repair cross-complementation group 1 (XRCC1) Arg399Gln gene in the pathogenesis of Systemic Lupus Erythematosus (SLE). Methods: The study was a case-control study carried out on 100 recently diagnosed SLE patients compared to 100 control subjects. The study of XRCC1 Arg399Gln polymorphism was performed by a polymerase chain reaction and restriction fragment length polymorphism. Results and Discussion: A higher frequency of ‘G’ allele in SLE (38.5%) versus control (32%) was noticed; however, this difference was not statistically significant (p = 0.174). Besides, a slightly higher frequency of G/G genotype was found in SLE (22%) vs. control (12%); again, this difference was not statistically significant (p = 0.157). A statistically significantly higher proportion of arthritis, serositis, and thrombocytopenia was observed in the A/A genotype (p = 0.010, 0.032, and 0.036, respectively). Furthermore, we noticed a statistically significant lower hemoglobin level in G/G genotype (p = 0.027). Otherwise, there was no statistically significant difference between the three genotypes regarding other parameters: photosensitivity, malar rash, oral ulceration, ANA, anti-dsDNA antibody, anemia, leucopenia, neurologic manifestations, and all lab parameters except hemoglobin level. Similar results were reported previously. According to genotype, in the study of Clinical and laboratory parameters in SLE patients, a statistically significantly higher proportion of arthritis, serositis, and thrombocytopenia was observed in the A/A genotype (p =0 .01, 0.032, and 0.036 respectively). Furthermore, we noticed a statistically significant lower hemoglobin level in G/G genotype (p = 0.027). These findings suggest a pathogenic connection between the seriousness of the defective DNA repair and the autoimmune severity; such connection is consistent with that found in several murine models. Additionally, negative regulation of the genes encoding the proteins involved in the NER pathway in SLE patients, specifically and XPC, has been found previously. Conclusion: The present study highlights the higher insignificant increase of G allele and GG genotype of XRCC1 399 gene in patients with SLE compared to healthy control. This increase was significantly associated with anemia in patients, which may reflect the aggravation of environmental risk factors to SLE associated with the reduced repair of DNA. Further longitudinal studies are required to validate the present findings.

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DNA Damage and Deficiencies in the Mechanisms of Its Repair: Implications in the Pathogenesis of Systemic Lupus Erythematosus

Cited by 26 publications

References 127 publications

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Gene Polymorphism of XRCC1 in Systemic Lupus Erythematous

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