DNA Damage Response and Repair in Adaptive Immunity

Abstract

The diversification of B-cell receptor (BCR), as well as its secreted product, antibody, is a hallmark of adaptive immunity, which has more specific roles in fighting against pathogens. The antibody diversification is from recombination-activating gene (RAG)-initiated V(D)J recombination, activation-induced cytidine deaminase (AID)-initiated class switch recombination (CSR), and V(D)J exon somatic hypermutation (SHM). The proper repair of RAG- and AID-initiated DNA lesions and double-strand breaks (DSBs) is required for promoting antibody diversification, suppressing genomic instability, and oncogenic translocations. DNA damage response (DDR) factors and DSB end-joining factors are recruited to the RAG- and AID-initiated DNA lesions and DSBs to coordinately resolve them for generating productive recombination products during antibody diversification. Recently, cohesin-mediated loop extrusion is proposed to be the underlying mechanism of V(D)J recombination and CSR, which plays essential roles in promoting the orientation-biased deletional end-joining . Here, we will discuss the mechanism of DNA damage repair in antibody diversification.

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

“…The Ig diversification derives from RAG1/2‐mediated V(D)J recombination and AID‐mediated CSR, and somatic hypermutation (SHM). 121 , 122 V(D)J recombination is a process to generate functional B‐cell (Ig) and T‐cell receptors 123 , 124 and naive B lymphocytes can transform into different isotypes under the antigen stimulation through CSR. 16 Next, we will discuss the role of DNA‐PKcs in V(D)J and CSR.…”

“… 151 cNHEJ is the main DSB end‐joining pathway during CSR. 121 The cNHEJ pathway is utilized by naive B cells to generate different isotypes of antibodies by joining two DNA double‐strand breaks at different switching regions via CSR. 17 Besides the core cNHEJ factors, Artemis and DNA‐PKcs are also important for joining AID‐initiated DSB repair during CSR.…”

“…CSR event involves the generation of DSB repair and joining between the donor (µ) and acceptor (γ, ε, or α) S regions to generate the new arrangement 151 . cNHEJ is the main DSB end‐joining pathway during CSR 121 . The cNHEJ pathway is utilized by naive B cells to generate different isotypes of antibodies by joining two DNA double‐strand breaks at different switching regions via CSR 17 .…”

Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens

“…Appropriate regulation of DNA repair is critical to successful immunoglobulin VDJ recombination, somatic hypermutation (SHM) and class switch recombination (CSR) in the early stages of plasma cell development [94,95]. Since DNA damaging agents are widely used in the treatment of MM [96], it is also not surprising that the expression levels of DNA repair proteins can predict responses to such agents [97,98].…”