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At the intersection of DNA damage and immune responses

Abstract

DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of lymphocyte antigen receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.

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Fig. 1: V(D)J recombination.
Fig. 2: B cell development.
Fig. 3: Large pre-B cell to small pre-B cell transition.
Fig. 4: Ordered assembly of antigen receptor genes.
Fig. 5: The toggle model.
Fig. 6: Immunoglobulin class switch recombination.
Fig. 7: Activation of the ncDDR in macrophages.

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Acknowledgements

This work was supported by US National Institutes of Health grants AI047829 (B.P.S.), AI074953 (B.P.S.) and K08AI102946 (J.J.B.). J.J.B. was supported by an Alex’s Lemonade Stand Foundation A Award, an American Society of Hematology Scholar Award, the Foundation for Barnes-Jewish Hospital, the Cancer Frontier Fund and the Barnard Trust.

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Nature Reviews Immunology thanks R. Casellas, J. Chaudhuri and M. Clark for their contribution to the peer review of this work.

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Glossary

Programmed DNA double-strand breaks

DNA double-strand breaks made at specific genomic regions as required intermediates of physiological processes, such as V(D)J recombination or immunoglobulin class switch recombination.

Non-programmed DNA DSBs

DNA double-strand breaks (DSBs) made by genotoxic agents or nucleases throughout the genome.

Canonical DNA damage response

(cDDR). A cellular response to DNA double-strand breaks (DSBs) initiated by DNA damage response kinases in all cells that activates the pathways required for DNA DSB repair and genome stability.

Non-homologous end joining

(NHEJ). A DNA repair process that joins broken DNA ends (double-strand breaks) at all phases of the cell cycle without using homologous DNA as a template. The core components of this pathway include the proteins KU70, KU80, X-ray repair cross-complementing protein 4 (XRCC4) and DNA ligase IV.

Non-canonical DNA damage responses

(ncDDRs). Cellular responses to DNA double-strand breaks (DSBs) activated by DNA damage response kinases but that are not involved in DNA DSB repair or in maintaining genome integrity. Rather, these DSB-dependent programmes regulate cell type-specific pathways that are involved in a broad variety of cellular functions.

Pre-B cell receptor

(Pre-BCR). A receptor composed of immunoglobulin heavy chains and surrogate light chains, VpreB and λ5, that associates with the transmembrane Igα and Igβ proteins that have cytoplasmic domains that transduce intracellular signals through the tyrosine kinase SYK and adaptor protein B cell linker protein (BLNK).

IL-7 receptor

(IL-7R). A receptor composed of the IL-7Rα chain and the cytokine receptor common γ-chain. Upon binding to IL-7, IL-7R activates the kinase AKT and the kinases Janus kinase 1 (JAK1) and JAK3, which phosphorylate and activate signal transducer and activator of transcription 5 (STAT5), to regulate cellular proliferation and survival.

Accessibility

Refers to the structure of chromatin. When chromatin is more loosely packed (or open), it is accessible for transcription, whereas tightly packed or closed chromatin is refractory to factors that need to gain access to the DNA template. Recombination-activating gene (RAG) is expressed in developing B and T cells, but it can only carry out V(D)J recombination at antigen receptor loci with an accessible chromatin structure.

ETS family transcription factors

A large family of proteins with conserved DNA binding domains that bind to GGA(A/T) (PU-box) motifs. Family members have distinct transactivation domains that dictate binding partners and regulate transcription. The PU.1 (also known as SPI1), SPIB and SPIC ETS family members all have roles in regulating transcription during B cell development.

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Bednarski, J.J., Sleckman, B.P. At the intersection of DNA damage and immune responses. Nat Rev Immunol 19, 231–242 (2019). https://doi.org/10.1038/s41577-019-0135-6

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