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  • Review Article
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The role of double-strand break repair — insights from human genetics

Nature Reviews Genetics volume 7, pages 45–54 (2006)Cite this article

Key Points

  • DNA-damage-response mechanisms encompass pathways of DNA-repair and signal-transduction processes that regulate cell-cycle-checkpoint arrest and/or apoptosis. The signal-transduction processes can regulate at least some aspects of DNA repair.

  • There are two main double-strand break (DSB) repair pathways — homologous recombination and non-homologous end-joining (NHEJ).

  • The main signal-transduction pathway that responds to a DSB is regulated by ataxia telangiectasia mutated (ATM), the protein that is defective in the hereditary disorder ataxia telangiectasia. Ataxia telangiectasia and RAD3-related (ATR) probably also has a supporting role in the response to DSBs.

  • Coupling occurs between ATM-dependent signalling and DSB repair. ATM regulates Artemis-dependent processing of a subset of DNA ends, which is required before rejoining by NHEJ can occur.

  • Several human congenital disorders with defects in damage-response mechanisms to DSBs have been described. These include, LIG4 syndrome, severe combined immunodeficiency with sensitivity to ionizing radiation, ataxia telangiectasia, ataxia telangiectasia-like disorder, Nijmegen breakage syndrome, ATR-Seckel syndrome and Fanconi anaemia, as exemplified by FANCD1 (Fanconi anaemia complementation group D1) deficiency.

  • These disorders are associated with a pleiotropic range of clinical features that demonstrate the important role that the damage-response processes have during development. Clinical features include immunodeficiency, development delay and microcephaly, cancer development and premature ageing.

  • The damage-response mechanisms function to maintain genomic stability in somatic cells. During V(D)J recombination and class-switch recombination, the damage-response proteins function to enhance genomic diversity at defined regions. Therefore, immunodeficiency is observed in some of the human DSB-repair-defective disorders.

  • Assays for diagnosis of damage-response disorders are now available and strategies for palliative treatment are beginning to emerge.

Abstract

The efficient repair of DNA double-strand breaks is crucial in safeguarding the genomic integrity of organisms. Responses to double-strand breaks include complex signal-transduction, cell-cycle-checkpoint and repair pathways. Defects in these pathways lead to several human disorders with pleiotropic clinical features. Dissection of the molecular basis that underlies the diverse clinical features is enhancing our understanding of the damage-response mechanisms and their role in development, and might ultimately facilitate treatment.

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Figure 1: Pathways that respond to double-strand breaks.

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Authors and Affiliations

  1. Genome Damage and Stability Centre, University of Sussex, East Sussex, BN1 9RQ, UK

    Mark O'Driscoll & Penny A. Jeggo

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  1. Mark O'Driscoll
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DATABASES

OMIM

ataxia telangiectasia

ataxia telangiectasia-like disorder

Fanconi anaemia complementation group D1

LIG4 syndrome

Nijmegen breakage syndrome

Omenn syndrome

Seckel syndrome

severe combined immunodeficiency with sensitivity to ionizing radiation

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy

TP53BP1

Glossary

V(D)J recombination

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. DNA double-strand breaks are introduced between the V, D and J segments and DNA-repair proteins then join the segments together.

Class-switch recombination

A recombination process that occurs on V(D)J recombined products, generating distinct immunoglobin isotypes.

Checkpoint arrest

Arrest at a specific stage of the cell cycle wherein the cell ensures that the previous stage has been completed normally or detects the presence of DNA damage.

Resection

A process in which a nuclease processes DNA double-strand breaks to create single-stranded overhangs.

Lymphoblastoid cell lines

Cell lines that are obtained from B lymphocytes — a fraction of white cells from blood that can be grown indefinitely in the laboratory after special treatment of the cells with Epstein–Barr virus.

Holliday junction

The cross-over point at which the two complementary strands that are derived from separate DNA molecules form during homologous recombination.

Pulsed-field gel electrophoresis

A technique for separating DNA of high molecular weight by gel electrophoresis in which the current is applied in pulses in alternating directions.

Confluency

A stage of cell growth during which cell division and DNA replication is inhibited by contact inhibition between cells in culture.

Monoubiquitylation

Post-translational modification in which a single ubiquitin moiety is added to lysine residues. Polyubiquitylation, which generates ubiquitin chains, targets proteins for proteasome-mediated degradation.

Somatic hypermutation

A process that occurs after immunoglobulin gene rearrangement, whereby the base sequences of part of the immunoglobulin variable regions are mutated more frequently than the rest of the genome. This sequence variation is subject to a selection process in the immune system that favours those cells that express immunoglobulins with the highest affinity for the antigen.

Pancytopenia

Reduced numbers of all types of blood cell.

Occipitofrontal circumference

The circumference of the head as measured from the forehead to the back of the head (occipital bone).

Ataxia

A failure or irregularity of muscular coordination.

Purkinje neurons

A class of large ganglion neurons in the cerebellum.

Kyphosis

A posterior or backwards orientated curvature of the thoracic region of the spine.

Psoriasis and squamous patches

A generally localized dry scaling or appearance of plate-like layers on the skin.

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O'Driscoll, M., Jeggo, P. The role of double-strand break repair — insights from human genetics. Nat Rev Genet 7, 45–54 (2006). https://doi.org/10.1038/nrg1746

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