DNA Damage Response in the Adaptive Arm of the Immune System: Implications for Autoimmunity

Abstract

In complex environments, cells have developed molecular responses to confront threats against the genome and achieve the maintenance of genomic stability assuring the transfer of undamaged DNA to their progeny. DNA damage response (DDR) mechanisms may be activated upon genotoxic or environmental agents, such as cytotoxic drugs or ultraviolet (UV) light, and during physiological processes requiring DNA transactions, to restore DNA alterations that may cause cellular malfunction and affect viability. In addition to the DDR, multicellular organisms have evolved specialized immune cells to respond and defend against infections. Both adaptive and innate immune cells are subjected to DDR processes, either as a prerequisite to the immune response, or as a result of random endogenous and exogenous insults. Aberrant DDR activities have been extensively studied in the immune cells of the innate arm, but not in adaptive immune cells. Here, we discuss how the aberrant DDR may lead to autoimmunity, with emphasis on the adaptive immune cells and the potential of therapeutic targeting.

ATR-mediated DNA damage responses underlie aberrant B cell activity in systemic lupus erythematosus

“…The main transducers of the DDR signaling are the three protein kinases ATM (ataxia-telangiectasia mutated), ATR (ATM and Rad3 related), and DNA-PKcs (DNA-dependent protein kinase catalytic subunit) (7). ATM and DNA-PKcs are considered as the pinnacles of the double-strand DNA breaks signaling cascade, whereas ATR is mainly activated upon single-strand DNA breaks and responds to agents causing DNA replication stress, such as ultraviolet light (8,9). Upon activation, these DDR components may phosphorylate separately or synergistically a number of proteins including checkpoint kinase 2 (Chk2; Thr 68 , by ATM), Chk1 (Ser 345 , by ATR), H2AX (Ser 139 , Η2ΑΧ) and p53 (Ser 15 ), determining cellular response and fate (8).…”

“…ATM and DNA-PKcs are considered as the pinnacles of the double-strand DNA breaks signaling cascade, whereas ATR is mainly activated upon single-strand DNA breaks and responds to agents causing DNA replication stress, such as ultraviolet light (8,9). Upon activation, these DDR components may phosphorylate separately or synergistically a number of proteins including checkpoint kinase 2 (Chk2; Thr 68 , by ATM), Chk1 (Ser 345 , by ATR), H2AX (Ser 139 , Η2ΑΧ) and p53 (Ser 15 ), determining cellular response and fate (8). Notably, p95/NBS1 (also called nibrin) usually colocalizes with Η2ΑΧ at the damaged genomic site and may propagate both ATR-and ATM-dependent signaling (10,11).…”

“…On the basis of the above, a currently unmet need is the understanding of the molecular events that operate in pathogenic B cell clones, which will allow their selective targeting, leaving the healthy B cell repertoire unaffected to mediate immune protection. Although B cells are prone to DDR errors because DDR is co-opted in antibody diversification (8) and accumulating evidence reports inefficient DDR in leukocytes from patients with SLE, the molecular links of B cell DDR with the pathophysiology of autoimmune diseases are ill-defined (3)(4)(5)(24)(25)(26). ATM down-regulation in B cells of patients with RA mediates a pro-ostoeclastogenic B cell phenotype driving erosive disease (6).…”

Survivin in Synergy With Baf/Swi Complex Binds Bivalent Chromatin Regions and Activates Dna Damage Response in Cd4+ T Cells

“…Evaluation of intervention in the DNA damage response pathway induced by immunomodulating RA treatment affected the transcriptional effects of survivin-containing BvCR in assisting IFN signaling in CD4 + T cells. Activation of DNA damage response is a crucial characteristic of autoimmune CD4 + T cells, which accumulate impaired DNA repair, induction of apoptosis, and abnormal metabolism (Shao, 2018; Manolakou et al, 2021). Methotrexate treatment mildly diverged DNA damage response but JAKi strongly upregulated DNA damage signaling, together suggesting that immunomodulating treatment intervene in these IFN-dependent processes in CD4 + cells.…”

Antiviral Innate Immune Responses in Autoimmunity: Receptors, Pathways, and Therapeutic Targeting

“…SAMHD1 protein is known to restrict HIV-1 infection in cells of the myeloid lineage, such as monocytes/macrophages and DCs, by inhibiting the synthesis of viral DNA. AGS mimics congenital viral infection as defective nucleases in AGS are involved in the deficient removal of endogenous nucleic acids resulting in the accumulation of ssDNA and the chronic activation of the innate immune response and the DNA damage response network [ 135 , 136 , 137 ]. The phenotypic overlap of AGS with congenital infection and some traits of SLE pathogenesis highlights the IFN-α-mediated immune response upon viral and host nucleic acids triggering the PRR signaling cascades [ 138 ].…”