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  • Review Article
  • Published:

DNA damage: a trigger of innate immunity but a requirement for adaptive immune homeostasis

Nature Reviews Immunology volume 6, pages 261–270 (2006)Cite this article

Key Points

  • DNA double-stranded break (DSB) damage activates ataxia-telangiectasia mutated (ATM)-dependent cell-cycle checkpoints, leading to cell-cycle arrest and efficient DNA repair. The DNA DSB damage is repaired mainly by the non-homologous end-joining pathway in mammalian cells.

  • Viral infection induces DNA-damage responses to DSBs that arise in infected host cells. These DNA-damage responses are required for the survival of host cells, but they can have either a positive or a negative effect on productive infection, depending on the type of virus.

  • DNA-damage responses activate innate immune responses through several pathways, including the upregulation of expression of NKG2D (natural killer group 2, member D) ligands and interferon-regulatory factors.

  • DNA DSBs are necessary intermediates of V(D)J recombination. They are required for generation of the large repertoire of antigen-specific cells that are the main components of the adaptive arm of the immune system. DNA-damage responses to DSBs have important roles in efficient V(D)J recombination and in prevention of recombination-activating gene (RAG)-protein-induced genetic instability in lymphocytes.

  • Activation-induced cytidine deaminase (AID)-induced DNA lesions are required for both class-switch recombination and somatic hypermutation. DNA-damage responses to DSBs are important for class-switch recombination but dispensable for somatic hypermutation.

  • Granzyme A and granzyme C are released by cytotoxic T lymphocytes and induce caspase-independent apoptosis of target cells, by activating pathways that introduce DNA DSBs into the genome of these cells.

Abstract

Chromosome breakage is frequently associated with viral infection and cellular transformation, but it is also required for two processes that are crucial for the development and function of adaptive immunity: V(D)J recombination and class-switch recombination. The cellular responses that result from this type of DNA damage, which are mostly activated by the protein kinase ataxia-telangiectasia mutated (ATM), lead to cell-cycle arrest at several checkpoints and efficient DNA repair. This Review focuses on the important roles of these DNA-damage responses in the activation of innate immunity and the targeting of the innate immune response to infected or transformed cells, as well as in the development and function of adaptive immunity.

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Figure 1: Activation of DNA-damage responses by DNA double-stranded-break damage.
Figure 2: Non-homologous end joining in vertebrate cells.
Figure 3: DNA-damage responses and cell-cycle regulation of V(D)J recombination.
Figure 4: DNA-damage responses during class-switch recombination.

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Acknowledgements

The author thanks C. Bassing and F. Alt for helpful discussion and critical reading of the manuscript. This work was supported by a grant from the National Institutes of Health (USA).

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    Yang Xu

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Glossary

Chromosomal translocation

Transfer of a segment of a chromosome to a different chromosome, often leading to an abnormal fusion gene or overexpression of one of the genes that is adjacent to the breakpoint.

Cell-cycle-checkpoint proteins

Proteins that regulate the progression of the cell cycle at three checkpoints: G1–S (the boundary between gap1 phase and synthesis phase), intra-S phase and G2–M (the boundary between gap 2 phase and mitosis phase).

Homologous recombination

Genetic recombination that occurs between strands of DNA with long stretches of homology.

Non-homologous end joining

A pathway that rejoins DNA strand breaks without relying on there being considerable homology between the strands. The main known pathway uses the Ku end-binding complex and is regulated by DNA-dependent protein kinase. The pathway is often used in mammalian cells to repair strand breaks caused by agents that damage DNA, and some of the same enzymes are used during the strand-joining steps of V(D)J recombination.

Ataxia-telangiectasia

A human autosomal recessive disease that is characterized by growth retardation, cerebellar degeneration, oculocutaneous telangiectasia, endocrine dysfunction, gonadal abnormalities, immunodeficiency, high cancer risk and hypersensitivity to ionizing radiation.

Meiotic recombination

The exchange of DNA strands between homologous chromosomes during meiosis.

Nijmegen breakage syndrome

A human autosomal recessive disease that is characterized by multisystem defects, including microcephaly, growth retardation, immunodeficiency and increased cancer risk.

Hypomorphic mutation

A type of mutation in which either the altered gene product has decreased activity or the wild-type gene product has reduced expression.

Microhomology-mediated NHEJ

An error-prone non-homologous end joining (NHEJ) mechanism that involves pairing of the overhanging ends, gap filling or deletion, and ligation of the ends.

Endonuclease

An enzyme that catalyses the hydrolysis of bonds between nucleotides in a DNA molecule.

Reverse transcribed

Reverse-transcriptase-mediated synthesis of DNA using RNA as the template.

Adenoviruses

Double-stranded DNA viruses that encode ∼30 viral proteins. The viral DNA is replicated and transcribed in the nucleus of host cells.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, ubiquitin can target proteins for degradation by the proteasome, sort them into specific subcellular compartments or modify their biological activity.

DNA transposition

The movement of DNA segments from one part of the genome to another.

Switch region

The DNA sequence that precedes each constant (C) gene segment in the immunoglobulin heavy-chain locus. It is involved in DNA rearrangement during class-switch recombination, leading to the expression of a different class of immunoglobulin.

RNA-editing enzyme

An enzyme that is involved in alteration of the nucleotide sequence of an RNA molecule.

DNA cytidine deaminase

An enzyme that catalyses the deamination of deoxycytidine residues into deoxyuridine residues.

Ligation-mediated PCR

(LM-PCR). A method that involves the ligation of unphosphorylated adaptors to broken DNA, followed by PCR. It can detect DNA double-stranded breaks in defined regions of the genome. It has been used extensively to analyse recombination-activating gene (RAG)-protein-dependent breaks during V(D)J recombination. More recently, it has been used to examine breaks in variable (V) gene segments and switch regions during somatic hypermutation and class-switch recombination, respectively.

Base-excision-repair pathway

A DNA-repair pathway that removes single bases from DNA, such as deoxyuridine residues that arise from deamination of deoxycytidine residues. Repair is initiated by a DNA glycosylase that is specialized for a particular class of damage.

Mismatch-repair pathway

A DNA-repair pathway that recognizes and corrects mismatched base pairs (typically those that arise from errors in chromosomal DNA replication).

Nucleoside diphosphate kinase

A house-keeping enzyme that is required for the synthesis of nucleoside triphosphates other than ATP.

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Xu, Y. DNA damage: a trigger of innate immunity but a requirement for adaptive immune homeostasis. Nat Rev Immunol 6, 261–270 (2006). https://doi.org/10.1038/nri1804

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