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.
Highlights
The B cells from systemic autoimmune rheumatic disease (SARD) patients may generate autoantibodies against DNA damage response (DDR)-related proteins, suggesting that B cells respond to quiescent or lasting DNA damage preceding or during the development of overt disease. These autoantibodies are directed against Ku, MRE11A, PARP, WRN, p53, PMS1, PMS2, MLH1, and other nuclear proteins that are implicated in the DDR, and their deregulated expression levels have been associated with defective DNA repair [51,61,62]
This study provides robust evidence that expression derangement of DDR-associated genes involved mainly in B cell physiology can be associated with autoimmune phenotypes
Further research is needed to expand our knowledge regarding the role of the DDR in the pathogenesis of autoimmune diseases
Summary
The DNA damage response (DDR) is a mechanism that consists of multiple signal transduction pathways required to meet the challenge of passing down undamaged DNA to subsequent generations and, maintaining genomic stability [1,2]. This response mechanism faces, every day, tens of thousands of damaged DNA lesions per cell [3,4,5] by activating a complex, dynamic and structured cascade (Figure 1) In this cascade of events, the DNA sensors molecules (e.g., RPA, Ku, MRN complex) recognize specific genome modifications (base mismatches, single-stranded DNA breaks, DNA adducts, double-stranded DNA breaks) and recruit the following reinforcements: (i) proteins that accumulate at the detected damaged sites and transduce the signal (e.g., ATM, ATR, DNAPKcs, γH2AX, 53BBP1) and (ii) effector molecules (e.g., CHK2, CHK1, p53, RAD51, BRCA1) that carry out the critical outcome of the cascade [2,6]. Depending on the mechanism’s efficiency, it is likely that the damage may result in impaired cellular function
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