DNA Double-Strand Break Repair Mechanisms in Lymphocyte Development

Lymphocyte development relies on the deliberate induction and precise repair of DNA double-strand breaks (DSBs) to generate the diverse repertoire of antigen receptors that underpin adaptive immunity. Two sequential processes, V(D)J recombination in developing B and T cells and class-switch recombination in mature B cells, both exploit DSBs introduced by specialised nucleases. Repair is predominantly executed by classical non-homologous end-joining (NHEJ), a rapid, template-independent pathway assembling broken DNA ends via core factors such as KU70/KU80, DNA-PKcs, XRCC4 and DNA ligase IV. When classical NHEJ is compromised, an alternate end-joining mechanism (alt-NHEJ) mediated by microhomology usage and polymerase θ can restore breaks, albeit with increased risk of genomic instability. At each developmental stage, the cellular DNA damage response (DDR) kinases ATM, ATR and DNA-PKcs coordinate end recognition, signalling and cell-cycle checkpoint control to ensure breaks are faithfully repaired without compromising cellular proliferation. Dysregulation of these repair pathways not only impairs lymphocyte maturation—leading to immunodeficiency—but also predisposes to chromosomal translocations and lymphoid malignancies. Recent advances have illuminated the interplay of repair factors, the choice between competing pathways and the impact of cell-cycle context on repair fidelity, offering new insights into immune diversification, genome stability and the design of targeted therapies.

Research from Nature Portfolio

Recent studies have uncovered an unexpected role for the ATR kinase in supporting normal proliferation of unstressed naïve B cells. Rather than solely responding to replication stress, ATR temperates the pace of replication origin firing during early S phase to prevent depletion of nucleotides and ensure DNA synthesis proceeds efficiently, a process critical for rapid expansion of lymphocyte precursors. In parallel, work on induced G1 DSBs has revealed that breaks carried into S–G2/M phases are repaired by polymerase θ-dependent alt-NHEJ. This pathway operates independently of PARP1, utilises long end resection and microhomologies, and becomes essential when classical NHEJ factors such as XRCC4 are absent, driving repair events that may fuel genomic rearrangements. Together these findings broaden our understanding of how lymphocyte precursor cells navigate replication and break repair to preserve genome integrity during immune development.

DNA Double-Strand Break Repair Mechanisms in Lymphocyte Development publication trend

The graph below shows the total number of articles in dna double-strand break repair mechanisms in lymphocyte development across all publications each year (not limited to Nature Index journals).

Technical terms

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, requiring specialised repair pathways to prevent loss of genetic information.

Non-homologous end-joining (NHEJ): A primary DSB repair pathway that ligates broken ends directly without the need for extensive homology, critical for V(D)J recombination and class-switch recombination.

Alternative NHEJ (alt-NHEJ): A backup DSB repair mechanism using microhomology at resected ends and polymerase θ, often engaged when classical NHEJ factors are deficient.

V(D)J recombination: The process in developing lymphocytes that assembles diverse antigen receptor genes by cutting and joining variable (V), diversity (D) and joining (J) gene segments.

Class-switch recombination (CSR): A mechanism in mature B cells that exchanges the antibody constant region to alter effector function, initiated by activation-induced cytidine deaminase and resolved by NHEJ.

References

1. ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion. Nature Communications (2023).
2. ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion. Cell & Bioscience (2020).
3. Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy. Frontiers in Immunology (2021).
4. Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ. Nature Communications (2020).
5. Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome. Journal of Experimental Medicine (2020).