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The emerging role of nuclear architecture in DNA repair and genome maintenance

Nature Reviews Molecular Cell Biology volume 10, pages 243–254 (2009)Cite this article

Key Points

  • DNA repair occurs in the context of higher-order chromatin structure.

  • The assembly of the DNA-repair machinery on damaged chromatin is a spatially and temporally highly coordinated event.

  • Sites of DNA repair manifest themselves as DNA-repair foci, which form as a consequence of the accumulation of repair factors at sites of damage and serve to amplify the damage signal.

  • Histone modifications, histone exchange and chromatin remodelling are essential steps in DNA repair.

  • In mammalian cells, double-stranded DNA breaks (DSBs) are positionally stable and do not migrate in the nuclear space. In yeast, DSBs can migrate and multiple DSBs coalesce in repair centres.

  • The non-random spatial organization of the genome contributes to the translocation frequency of chromosomes in vivo.

Abstract

DNA repair and maintenance of genome stability are crucial to cellular and organismal function, and defects in these processes have been implicated in cancer and ageing. Detailed molecular, biochemical and genetic analyses have outlined the molecular framework involved in cellular DNA-repair pathways, but recent cell-biological approaches have revealed important roles for the spatial and temporal organization of the DNA-repair machinery during the recognition of DNA lesions and the assembly of repair complexes. It has also become clear that local higher-order chromatin structure, chromatin dynamics and non-random global genome organization are key factors in genome maintenance. These cell-biological features of DNA repair illustrate an emerging role for nuclear architecture in multiple aspects of genome maintenance.

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Figure 1: Assembly of DNA-damage response complexes.
Figure 2: DNA-repair foci and their dynamics.
Figure 3: Chromatin events during DNA repair.
Figure 4: DNA repair in the context of nuclear architecture.
Figure 5: Models of chromosome translocations.

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Acknowledgements

We thank V. Roukos for critically reading the manuscript. Misteli's laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research. Soutoglou's laboratory is supported by the National Centre for Scientific Research and Institute of Genetics and Molecular and Cellular Biology.

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Authors and Affiliations

  1. National Cancer Institute, NIH, Bethesda, 20892, Maryland, USA

    Tom Misteli

  2. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 596, Illkirch, Cedex, CU de Strasbourg, France

    Evi Soutoglou

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Glossary

D-loop

A DNA structure in which the two strands of a double-stranded DNA are separated by a third strand. It is created after strand invasion during homologous recombination.

Holliday junction

A mobile junction between four strands of DNA, with homology between pairs of neighbouring DNA molecules.

Histone variant

A core histone other than the classical histones (H2A, H2B, H3 or H4).

Chromatin-remodelling complex

A protein complex that alters the higher-order structure of the chromatin fibre by changing its compaction or repositioning nucleosomes, often using ATP hydrolysis.

Clamp loader

A protein that loads the clamp complex onto the DNA.

Clamp complex

A protein complex that wraps around DNA and facilitates the processivity of DNA replication.

Nucleotide-excision repair

The repair mechanism that removes damaged single nucleotides, mostly in response to ultraviolet damage.

Histone deacetylase

An enzymatic activity that removes an acetyl group from a histone tail.

Histone acetyl transferase

An enzymatic activity that adds an acetyl group to a histone tail.

Heterochromatin

Compact, closed chromatin that generally contains silenced genome regions.

Euchromatin

Decondensed, open chromatin that generally contains transcriptionally active genome regions.

Histone methyltransferase

An enzymatic activity that adds a methyl group to a histone tail.

V(D)J recombination

A recombination reaction that assembles genes encoding diverse T-cell receptor and immunoglobulin molecules from variable (V), diversity (D) and joining (J) gene segments. V(D)J recombination is necessary for the recognition of diverse foreign antigens.

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Misteli, T., Soutoglou, E. The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat Rev Mol Cell Biol 10, 243–254 (2009). https://doi.org/10.1038/nrm2651

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