|DNA in our cells is constantly damage by internal and external factors generating DSBs. To maintain genome stability, cells have developed various DNA damage surveillance and repair mechanisms to prevent chromosomal aberrations that have been shown to promote cancer and cell death.
During B and T cell development, the major DSBs repair pathway, classical Non-Homologous End-Joining (C-NHEJ) pathway, is required to repair DSBs occurring during physiological processes. In particular, in lymphocytes undergoing maturation in bone marrow, DSBs are introduced on purpose by the RAG endonuclease at V (variable), D (diversity) and J (joining) gene segments of heavy and light chains of immunoglobulin variable regions. Their repair leads to the assembly of numerous V, D and J genes segments in different combinations during the V(D)J recombination to contribute to diverse antibodies and antigen receptor repertoires. In the periphery, antigen-activated mature B lymphocytes undergo immunoglobulin heavy-chain (IgH) class switch recombination (CSR). The CSR allows B cells to express different classes of antibodies with different IgH constant regions and, as a result, different antibody effectors functions. CSR is initiated by Activation-induced cytidine deaminase (AID), which introduces DSBs at S regions of transcribed IgH joined by the C-NHEJ pathway. Mutations in genes encoding some C-NHEJ factors impairs DSBs repair and abrogates lymphocytes development (Artemis, DNA-PKcs, Ligase 4 and XLF) resulting in immunodeficiency, underscoring the importance of this pathway in mammalian cells.
DNA breaks also activate the DDR pathway to maintain the genome integrity. Multiple enzymes of the DDR pathway catalyze post-translational modifications of DDR and NHEJ factors and histones at chromatin surrounding the break to regulate the transcription, replication and DNA repair (ATM, DNA-PKcs, H2AX and MDC1). Gcn5 and PCAF acetyltransferases were also describe to participate in the DDR pathway by the regulation of the gene activation through the acetylation of histone H3 at lysine 9 (H3K9ac) and are functionally redundant (Lee et al., 2010; Jin et al., 2011). Some DDR factors were described to regulate some aspects of the V(D)J recombination (ATM, DNA-PKcs, H2AX and 53BP1) and mutations in very few genes encoding DDR proteins have been linked to immunodeficiency. However, the molecular mechanism causing this phenotype is unknown, because many of DDR factors have overlapping functions that complicates loss-of function analyses.