Abstract
Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double-strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, MRI) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.
Highlights
DNA double strand breaks (DSBs) are generated both extrinsically, e.g. by chemotherapeutic agents; and physiologically, for example, during the V(D)J recombination in developing B and T lymphocytes, and class switch recombination (CSR) in activated mature B cells [1,2].DNA damage response (DDR) pathway operates upon the DSBs induction
Phosphorylated H2AX facilitates the recruitment of modulator of DNA damage checkpoint 1 (MDC1), following the activation of really interesting protein (RING) finger 8 (RNF8) and RNF168, which are ubiquitin ligases
During the early stages of B and T cell development, non-homologous end joining (NHEJ) is required for the V(D)J recombination assembling immunoglobulin (Ig) and T cell receptor (TCR) genes using V, D, and J gene segments (Figure 1B)
Summary
DNA double strand breaks (DSBs) are generated both extrinsically, e.g. by chemotherapeutic agents; and physiologically, for example, during the V(D)J recombination in developing B and T lymphocytes, and class switch recombination (CSR) in activated mature B cells [1,2]. Ataxia telangiectasia mutated (ATM) is a DDR regulator protein kinase that phosphorylates multiple substrates in response to the DSBs, including histone H2AX, modulator of DNA damage checkpoint 1 (MDC1), and p53-binding protein 1 (53BP1). During the early stages of B and T cell development, NHEJ is required for the V(D)J recombination assembling immunoglobulin (Ig) and T cell receptor (TCR) genes using V, D, and J gene segments (Figure 1B) Both Ig and TCR provide antigen-binding specificity required for an efficient immune response. Several mutations in genes encoding NHEJ factors were identified in human patients The features of these patients vary from mild immunodeficiency when XLF/CERNUNNOS is mutated, to severe combined immunodeficiency, delayed growth and neurological abnormalities in patients with defects in XLF, DNA-PKCS/PRKDC, ARTEMIS/DCLRE1C, XRCC4, and LIG4 [22]. Mutations in accessory factor genes, e.g. PAXX and MRI, might be tolerated without leading to clinical features
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