Abstract
Lymphocytes are endowed with unique and specialized enzymatic mutagenic properties that allow them to diversify their antigen receptors, which are crucial sensors for pathogens and mediators of adaptive immunity. During lymphocyte development, the antigen receptors expressed by B and T lymphocytes are assembled in an antigen-independent fashion by ordered variable gene segment recombinations (V(D)J recombination), which is a highly ordered and regulated process that requires the recombination activating gene products 1 & 2 (RAG1, RAG2). Upon activation by antigen, B lymphocytes undergo additional diversifications of their immunoglobulin B-cell receptors. Enzymatically induced somatic hypermutation (SHM) and immunoglobulin class switch recombination (CSR) improves the affinity for antigen and shape the effector function of the humoral immune response, respectively. The activation-induced cytidine deaminase (AID) enzyme is crucial for both SHM and CSR. These processes have evolved to both utilize as well as evade different DNA repair and DNA damage response pathways. The delicate balance between enzymatic mutagenesis and DNA repair is crucial for effective immune responses and the maintenance of genomic integrity. Not surprisingly, disturbances in this balance are at the basis of lymphoid malignancies by provoking the formation of oncogenic mutations and chromosomal aberrations. In this review, we discuss recent mechanistic insight into the regulation of RAG1/2 and AID expression and activity in lymphocytes and the complex interplay between these mutagenic enzymes and DNA repair and DNA damage response pathways, focusing on the base excision repair and mismatch repair pathways. We discuss how disturbances of this interplay induce genomic instability and contribute to oncogenesis.
Highlights
B-cell precursors are generated from hematopoietic stem cells (HSCs) in the liver during the fetal life and postnatally in the bone marrow (BM) through an ordered developmental pathway [1]
It has become clear that B cells both engage as well as counteract the DNA damage response (DDR) and the different DNA repair pathways in order to maximize antigen receptor diversity while minimizing collateral damage
The evolutionary trade-off between adaptive immunity and genomic integrity is underscored by the utilization of DNA repair pathways for mutagenic purposes in B cells
Summary
B-cell precursors are generated from hematopoietic stem cells (HSCs) in the liver during the fetal life and postnatally in the bone marrow (BM) through an ordered developmental pathway [1]. Upon encountering antigen in secondary lymphoid organs, B cells become activated and differentiate into memory B cells or antibody-secreting plasma cells These processes occur in the germinal center (GC), a specialized anatomical site that arises within lymphoid follicles, where Ig receptors undergo somatic hypermutation (SHM) and class switch recombination (CSR). The cleavage phase requires RAG1/2 endonuclease activity, which creates double-strand breaks (DSBs) at recombination signal sequences (RSS) adjacent to each antigen receptor gene segment. Functional Artemis deficiency in humans results in the absence of B and T cells and hypersensitivity to DNA damage, underscoring its crucial importance for V(D)J recombination [19]. The hairpin opening capacity of Artemis is activated by DNA protein kinase catalytic subunit (DNA-PKcs) phosphorylation, which orchestrates the non-homologous end joining (NHEJ) functions required for V(D)J recombination [19,20] (Figure 2). Next to a tight regulation of DSB repair during V(D)J recombination, the expression and activity of RAG itself is subject to intense regulation
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