DNA Repair Mechanisms in Immunodeficiency Disorders

Genomic integrity in lymphocytes relies on precise repair of DNA double-strand breaks (DSBs) introduced during antigen-receptor gene assembly and by exogenous insults. The non-homologous end joining (NHEJ) pathway, centred on proteins such as DNA ligase IV, XRCC4, XLF and the Artemis nuclease, is essential for sealing these breaks in developing T and B cells. Homologous recombination (HR) contributes to DSB repair in cycling progenitors, with defects in HR-associated factors leading to syndromes such as ataxia–telangiectasia characterized by immunodeficiency and neurodegeneration. Hypomorphic and monoallelic mutations in NHEJ components have been shown to produce a continuum of clinical phenotypes, from classical severe combined immunodeficiency to milder immune dysregulation accompanied by autoimmunity and radiosensitivity. Animal models lacking end-processing enzymes now faithfully mirror human immunodeficiencies, enabling in vivo studies of engraftment and gene-therapy approaches. Recognition of DNA repair disorders has guided therapeutic strategies, favouring reduced-intensity conditioning regimens for haematopoietic stem cell transplantation and the exploration of gene-editing technologies to correct repair defects. Current research efforts aim to identify modifier pathways that influence disease expressivity and to develop targeted interventions that restore genome stability while minimising treatment-related toxicity.

Research from Nature Portfolio

No recent Nature Portfolio content available.

DNA Repair Mechanisms in Immunodeficiency Disorders publication trend

The graph below shows the total number of articles in dna repair mechanisms in immunodeficiency disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Non-homologous end joining (NHEJ): A DNA repair pathway that ligates double-strand breaks without requiring a sister chromatid, crucial for V(D)J recombination in lymphocytes.

V(D)J recombination: A programmed process in developing B and T cells that generates diverse antigen-receptor gene sequences through site-specific cleavage and rejoining of variable (V), diversity (D) and joining (J) segments.

Haploinsufficiency: A genetic scenario in which a single functional allele of a gene does not produce sufficient protein to maintain normal function, leading to disease manifestations.

Artemis (DCLRE1C): An endonuclease that processes DNA hairpins and overhangs during NHEJ and V(D)J recombination; its deficiency causes radiosensitive severe combined immunodeficiency.

References

1. Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency. Journal of Allergy and Clinical Immunology (2023).
2. Dclre1c-Mutation-Induced Immunocompromised Mice Are a Novel Model for Human Xenograft Research. Biomolecules (2024).
3. Hematopoietic Stem Cell Transplantation for DNA Double Strand Breakage Repair Disorders. Frontiers in Pediatrics (2020).