Histone modifications in response to DNA damage

doi:10.1016/j.mrfmmm.2006.09.009

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 618, Issues 1–2, 1 May 2007, Pages 81-90

https://doi.org/10.1016/j.mrfmmm.2006.09.009 Get rights and content

Abstract

The packaging of the eukaryotic genome into highly condensed chromatin makes it inaccessible to the factors required for gene transcription, DNA replication, recombination and repair. Eukaryotes have developed intricate mechanisms to overcome this repressive barrier imposed by chromatin. Histone modifying enzymes and ATP-dependent chromatin remodeling complexes play key roles here as they regulate many nuclear processes by altering the chromatin structure. Significantly, these activities are integral to the process of DNA repair where histone modifications act as signals and landing platforms for various repair proteins. This review summarizes the recent developments in our understanding of histone modifications and their role in the maintenance of genome integrity.

Introduction

The eukaryotic genome is maintained as a nucleoprotein complex known as chromatin, which consists of positively charged histone proteins in addition to DNA. The basic unit of chromatin is the nucleosome which consists of 146 bp of DNA wrapped around an octamer containing two copies each of core histones H2A, H2B, H3 and H4. Histone H1, also called linker histone, locks the DNA at the entry and exit points from the nucleosome and further condenses chromatin. The packaging of eukaryotic DNA into chromatin solves the problem of accommodating the enormous length of DNA in the small nuclear space.

Each core histone in the nucleosome contains a globular domain and a highly dynamic N-terminal tail rich in basic residues, which protrudes out from the nucleosome. In addition, H2A also possesses a protruding C-terminal domain. Recent findings have shown that these tails do not contribute either to the structure or stability of nucleosomes but play an important role in folding of nucleosomal arrays into higher order chromatin structures [1]. The histone tails are the sites for a number of post-translational modifications like acetylation and ubiquitination of lysine (K) residues, phosphorylation of serines (S) and threonines (T), and methylation of lysines and arginines (R). These modifications can regulate each other and are recognized by specific protein modules [2]. Thus, different combinations of these modifications dictate specific biological readouts, which form the basis of the histone code hypothesis.

The packaging of DNA into chromatin affects all DNA-related processes such as replication, transcription, recombination and repair. The cell has developed various mechanisms by which chromatin structure can be manipulated to regulate access to DNA. These include (i) ATP-dependent chromatin remodeling, (ii) incorporation of histone variants into nucleosomes, and (iii) covalent histone modifications [3]. Chromatin remodeling by multisubunit complexes utilizes the energy from ATP hydrolysis to affect histone–DNA interactions. These complexes can slide nucleosomes on the DNA molecule, regulating access to specific sequences. Histone variants possess biophysical properties distinct from those of canonical core histones, and their substitution into nucleosomes can bring about alterations into the higher order chromatin structure. Covalent modifications of histones can alter the charge of specific residues, affecting the histone–histone and histone–DNA interactions, and can act as signals for binding of various protein complexes. For instance, bromodomains present in several transcriptional coactivators associate with specific acetylated lysine residues, while chromodomain-containing proteins bind to methylated lysines [2]. This review discusses such histone modifications, specifically focusing on their involvement in the repair of DNA double-strand breaks.

Section snippets

Histone modifications and DNA repair

Each day the cell is exposed to a number of agents both extrinsic (chemical agents, UV radiation, ionizing radiation) and intrinsic (reactive oxygen species, endogenous alkylating agents), which cause DNA damage. Breaks in DNA also result from collapsed DNA replication forks or from oxidative destruction of deoxyribose residues. Failure to repair such lesions leads to genomic instability and cancer. Among the different types of damage, DNA double-strand breaks (DSBs) are the most deleterious

Future directions

As mentioned above, it is tempting to draw a simplified model of chromatin dynamics during the repair of DNA breaks in eukaryotes. Nevertheless, things are not as clear and straightforward as it seems. The model of interplay between Ino80, Swr1, NuA4, H2AZ and H2AX is still very speculative. Experiments need to be done to support or modify this model in both yeast and mammalian systems. The reported implication of other chromatin modifiers and remodelers also has to be investigated further in

Acknowledgements

We are grateful to the editors for their understanding during preparation of this review. We also thank Nikita Avvakumov for critical reading of the manuscript and colleagues for stimulating discussions. Work in our lab is supported by grants from the Canadian Institutes of Health Research (CIHR). JC is a CIHR Investigator.

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