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The histone code at DNA breaks: a guide to repair?

Nature Reviews Molecular Cell Biology volume 6, pages 757–765 (2005)Cite this article

Key Points

  • The repair of chromosomal DNA double-strand breaks, which is essential for the maintenance of genomic stability, occurs within the context of chromatin. Histone modifications correlate with DNA damage and might therefore serve as a code for repair.

  • Chromatin-remodelling complexes and histone-modifying enzymes are recruited to the sites of DNA damage. Histone tails and core domains also show significant damage-correlated modifications, including acetylation, deacetylation, methylation, phosphorylation and ubiquitylation.

  • Histone H2A phosphorylation by the ATM/ATR kinase has a key role in the recruitment of the INO80 chromatin remodeller and in the loading of cohesin at sites of double-strand breaks. Cohesin loading near DNA double-strand breaks might be facilitated by both the Mre11 protein and its ligand, the chromatin remodelling complex RSC.

  • A histone remodeler related to INO80, the SWR1 complex, can exchange histone H2A for a variant known as Htz1. Genetics studies implicate SWR1 in DNA repair, and the analysis of a related complex in Drosophila, TIP60, indicates that TIP60 might replace phospho-H2Av with unmodified histone at sites of damage.

  • Histone acetylation and deacetylation by the NuA4 and Sin3–Rpd3 complexes, respectively, might help open compact nucleosomal fibers at the sites of DNA damage. Roles for other covalent modifications of histones in facilitating repair are suggested but not definitively proven.

  • Histone H3K79 and H4K20 methylation is important to allow the recruitment of the checkpoint adaptor proteins 53BP1 (mammals) and Crb2 (fission yeast), respectively, to the sites of damage. This links histone modification with checkpoint activation, as the adaptors seem to bind at the sites of damage to stimulate checkpoint effector kinase activation.

Abstract

Chromatin modifications are important for all cellular processes that involve DNA, including transcription, replication and DNA repair. Chromatin can be modified by the addition of adducts to histone tail residues or by nucleosome remodelling, which requires ATP-dependent chromatin-remodelling complexes. Although the role of these mechanisms in transcription is well studied, their impact on DNA repair has only recently become evident. One crucial chromatin modification, the phosphorylation of histone H2A, links the recruitment of histone modifiers and ATP-dependent chromatin-remodelling complexes to sites of DNA damage.

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Figure 1: Histone modifications that are implicated in the DNA damage response.
Figure 2: A model for the function of phosphorylated H2A at DNA double-strand breaks in budding yeast.
Figure 3: Composition of the Saccharomyces cerevisiae SWR1, INO80, NuA4 and human TIP60 complexes.

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Acknowledgements

The authors acknowledge the European Molecular Biology Organization (EMBO) and the International Human Frontier Science Program (HFSP) Organization for fellowships to H.v.A., and thank the Swiss Cancer League, the European RTN Checkpoints and Cancer, the Swiss National Science Foundation and the Novartis Research Foundation for their support. The authors also thank Brehon Laurent for sharing results before publication and apologize to all researchers whose work could not be discussed due to space limitations.

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Haico van Attikum & Susan M. Gasser

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  1. Haico van Attikum
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Correspondence to Susan M. Gasser.

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Related links

Related links

DATABASES

Saccharomyces Genome Database

Act1

Arp4

Arp5

Arp8

Bdf6

Bre1

CK2

Ddc2

Eaf1

Eaf2

Eaf3

Eaf5

Eaf7

Epl1

Esa1

Hat1

Htz1

HO

Ies3

INO80

Ku70

Ku80

Lig4

Lif1

Mec1

Mre11

Nhp10

Rad6

Rad9

Rad50

Rad51

Rad52

Rad53

Rad54

Rad57

Rad59

Rpd3

Rvb1

Rvb2

Scc1

Scc2

Scc3

Sin3

Smc1

Smc3

Ste20

SWR1

Tel1

Tra1

Xrs2

Yaf9

Yng2

Swiss-Prot

ATM

ATR

53BP1

BAF53

BRCA1

Chk1

Crb2

DMAP1

DNA-PKcs

Domino/p400

EPC1

GAS41

H2AX

H2AZ

ING3

MRG15

MRGBP

MST1

NBS1

p53

RuvB

Set9

TIP60

TRRAP

XRCC2

XRCC3

XRCC4

FURTHER INFORMATION

Susan Gasser's laboratory

Glossary

CHROMATIN

A higher-order structure of DNA folded around histone octamers and stabilized by linker histones and other factors.

NUCLEOSOME

The basic unit of chromatin composed of 147 bp of chromosomal DNA wrapped around an octamer that contains two copies of each histone H2A, H2B, H3 and H4, or appropriate histone variants.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). A technique that allows the study of protein–DNA interactions by the amplification of DNA sequences from complexes of crosslinked proteins and DNA, recovered by immunoprecipitation with antibodies against the proteins in question.

BROMODOMAIN

An evolutionary conserved protein domain that can bind to acetylated residues of histones.

SANT DOMAIN

An evolutionary conserved protein domain that is important for DNA and histone-tail binding.

CHROMODOMAIN

An evolutionary conserved protein domain that can bind to methylated residues of histones.

EUCHROMATIN

Decondensed regions of chromatin usually associated with active transcription.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that adds acetyl groups to lysine or arginine residues of a histone.

HISTONE DEACETYLASE

(HDAC). An enzyme that removes acetyl groups from lysine or arginine residues of a histone.

HETEROCHROMATIN

Condensed regions of chromatin usually associated with the repression of transcription and late replication.

HISTONE METHYLTRANSFERASE

An enzyme that adds methyl groups to lysine or arginine residues of histones.

TUDOR DOMAIN

An evolutionary conserved chromodomain-like protein domain that can bind to methylated residues of histones.

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van Attikum, H., Gasser, S. The histone code at DNA breaks: a guide to repair?. Nat Rev Mol Cell Biol 6, 757–765 (2005). https://doi.org/10.1038/nrm1737

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