Increased Sensitivity of PBMCs Isolated from Patients with Rheumatoid Arthritis to DNA Damaging Agents Is Connected with Inefficient DNA Repair

Abstract

Rheumatoid arthritis (RA) is a systemic, inflammatory disease of the joints and surrounding tissues. RA manifests itself with severe joint pain, articular inflammation, and oxidative stress. RA is associated with certain types of cancer. We have assumed that RA patients’ increased susceptibility to cancer may be linked with genomic instability induced by impaired DNA repair and sensitivity to DNA damaging agents. The aim of this work was to analyze the sensitivity of peripheral blood mononuclear cells (PBMCs) isolated from RA patients to DNA damaging agents: tert-butyl hydroperoxide (TBH), bleomycin, ultraviolet (UV) radiation, and methyl methanesulfonate (MMS) and calculate the repair efficiency. TBH induce oxidative DNA lesions repaired mainly by base excision repair (BER). Bleomycin induced mainly DNA double-strand breaks repaired by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). We included 20 rheumatoid arthritis patients and 20 healthy controls and used an alkaline version of the comet assay with modification to measure sensitivity to DNA damaging agents and DNA repair efficiency. We found an increased number of DNA breaks and alkali-labile sites in the RA patients compared to those in the controls. Exposure to DNA damaging agents evoked the same increased damage in both groups, but we observed statistically higher PMBC sensitivity to TBH, MMS, bleomycin as well as UV. Examination of the repair kinetics of both groups revealed that the DNA lesions induced by TBH and bleomycin were more efficiently repaired in the controls than in the patients. These data suggest impaired DNA repair in RA patients, which may accelerate PBMC aging and/or lead to higher cancer incidence among RA patients.

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

“…Cancer cells often exhibit dysregulations in DNA repair mechanisms. However, several studies also indicated enhanced DNA damage and DNA repair deficiencies in lymphocytes from RA patients [ 75 , 76 , 77 , 78 ]. In addition to studies investigating the role of different JAK inhibitors on DNA damage response pathways in primary cells from healthy donors or cancer cell lines, future trials also need to address the impact of JAKi on lymphocytes from patients with RA.…”

Construction of a Novel LncRNA Signature Related to Genomic Instability to Predict the Prognosis and Immune Activity of Patients With Hepatocellular Carcinoma

“…For instance, ATM activates the pentose phosphate pathway by promoting anti-oxidant defense and DNA repair ( 88 ); the p53-TIGAR axis suppresses glycolysis in FA HSCs, leading to an enhanced pentose phosphate pathway and cellular anti-oxidant function and, consequently, to reduced DNA damage and GI ( 89 ); the p38α stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1α ( 90 ). In addition, fructose metabolism, retinol metabolism, and rheumatoid arthritis are all related to GI ( 91 – 95 ). These findings indicate that our characteristics are intimately linked to the occurrence and development of GI.…”

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

“…In the mitochondria, the DNA glycosylase, OGG1 (mt-OGG1), can deoxidize ox-mtDNA, thereby maintaining mtDNA quality. mt-OGG1 overexpression significantly reduces ox-mtDNA content in the cytoplasm and mitochondria and inhibits NLRP3 activation ( 149 ), indicating the lack of DNA repair capacity in PBMCs of patients with RA ( 150 ). In the future, repairing specific DNA damage using clustered regularly interspaced short palindromic repeats (CRISPR) technology may produce a cure for patients with RA ( 151 ).…”