DNA Damage Response in Lymphocyte Development
Summary
During B and T lymphocyte development, antigen receptor diversity arises through V(D)J recombination, a process driven by the RAG1/2 endonuclease that introduces programmed double-stranded DNA breaks (DSBs). The DNA damage response (DDR) orchestrates detection, signalling and repair of these lesions, primarily via non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways. Key kinases such as ATM and DNA-PKcs activate cell cycle checkpoints and recruit repair factors to maintain genomic integrity while tolerating physiological DSBs. Tight regulation of DDR components is essential to prevent off-target breaks and chromosomal translocations that underlie lymphoid malignancies. Crosstalk between DDR and immune signalling, for instance through the cGAS–STING axis, further influences lymphocyte survival, differentiation and inflammatory responses. Disruption of DDR factors manifests as immunodeficiency or predisposition to cancer, highlighting the clinical relevance of understanding these pathways. Emerging insights into the balance between controlled DNA cleavage for receptor gene assembly and repair fidelity underpin advances in immunodeficiency diagnostics, targeted therapies in B cell lymphoma and optimisation of genome editing strategies.
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DNA Damage Response in Lymphocyte Development publication trend
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Technical terms
DNA Damage Response (DDR): Cellular network that detects, signals and repairs DNA lesions to preserve genome integrity.
Double-stranded DNA break (DSB): A discontinuity affecting both strands of the DNA helix, requiring coordinated repair.
V(D)J recombination: Process generating antigen receptor diversity by rearranging variable (V), diversity (D) and joining (J) gene segments.
RAG1/2 complex: Endonuclease that initiates programmed DSBs at antigen receptor loci in developing lymphocytes.
Non-Homologous End-Joining (NHEJ): Repair pathway that ligates broken DNA ends directly without a homologous template.
Homologous Recombination (HR): Error-free DSB repair mechanism using a homologous DNA sequence as a template.
References
- When DNA-damage responses meet innate and adaptive immunity. Cellular and Molecular Life Sciences (2024).
- RAG1/2 induces double‐stranded DNA breaks at non‐Ig loci in the proximity of single sequence repeats in developing B cells. European Journal of Immunology (2024).
- DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs. BMC Genomics (2013).
- Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma. Cells (2020).
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