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The molecular basis and disease relevance of non-homologous DNA end joining

Abstract

Non-homologous DNA end joining (NHEJ) is the predominant repair mechanism of any type of DNA double-strand break (DSB) during most of the cell cycle and is essential for the development of antigen receptors. Defects in NHEJ result in sensitivity to ionizing radiation and loss of lymphocytes. The most critical step of NHEJ is synapsis, or the juxtaposition of the two DNA ends of a DSB, because all subsequent steps rely on it. Recent findings show that, like the end processing step, synapsis can be achieved through several mechanisms. In this Review, we first discuss repair pathway choice between NHEJ and other DSB repair pathways. We then integrate recent insights into the mechanisms of NHEJ synapsis with updates on other steps of NHEJ, such as DNA end processing and ligation. Finally, we discuss NHEJ-related human diseases, including inherited disorders and neoplasia, which arise from rare failures at different NHEJ steps.

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Fig. 1: Overview of the non-homologous DNA end joining process.
Fig. 2: DSB repair pathway choice.
Fig. 3: Mechanisms of NHEJ synapsis.
Fig. 4: Various NHEJ end processing mechanisms.
Fig. 5: Disease-related NHEJ hypomorphic protein variants identified in humans.

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Acknowledgements

This work was supported by US National Institutes of Health grants (GM118009, CA196671, CA100504 and P30 CA014089 to M.R.L.; CA097096 and CA84442 to D.A.R; and R01 GM108119 to E.R.), American Cancer Society grant 130304-RSG-16-241-01-DMC (E.R.), and V Foundation for Cancer Research grant D2018-020 (E.R.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Dale A. Ramsden or Michael R. Lieber.

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Nature Reviews Molecular Cell Biology thanks Sathees Raghavan, Dongyi Xu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Homologous recombination

(HR). An important DNA double-strand break repair mechanism, which usually requires long homologous sequences.

Class switch recombination

(CSR). Recombination of the immunoglobulin heavy chain locus, which results in a switch of the expressed heavy chain isotype from IgM to IgA, IgE or IgG.

Microhomology

Short stretches of base pairs of complementarity between two broken DNA ends.

Synaptic complex

The complex formed by the two juxtaposed DNA ends of a double-strand break and related non-homologous end joining proteins.

X polymerases

A subtype of DNA polymerases that includes terminal deoxynucleotidyl transferase, polymerase-µ (Polµ), Polλ and Polβ.

N nucleotides

In V(D)J recombination, nucleotides added by the polymerase terminal deoxynucleotidyl transferase to the ends of coding DNA segments independently of a template.

Inverted repeats

Nucleotides that are added at a DNA double-strand break repair junction and are sometimes copied inversely from either of the two broken DNA ends.

T nucleotides

Nucleotides added at a DNA double-strand break repair junction, which are sometimes copied (directly or inversely) from either strand of either of the two broken DNA ends in a template-dependent manner.

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Zhao, B., Rothenberg, E., Ramsden, D.A. et al. The molecular basis and disease relevance of non-homologous DNA end joining. Nat Rev Mol Cell Biol 21, 765–781 (2020). https://doi.org/10.1038/s41580-020-00297-8

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