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REVIEW Chromatin Modifications and DNA Double-Strand Breaks Leukemia (2007) 21, 195–200 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu REVIEW Chromatin modifications and DNA double-strand breaks: the current state of play TC Karagiannis1,2 and A El-Osta3 1Molecular Radiation Biology, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 2Department of Pathology, The University of Melbourne, Parkville, Melbourne, Victoria, Australia and 3Epigenetics in Human Health and Disease, Baker Medical Research Institute, The Alfred Medical Research and Education Precinct, Prahran, Victoria, Australia The packaging and compaction of DNA into chromatin is mutated (ATM) and ataxia telangiectasia-related (also known as important for all DNA-metabolism processes such as transcrip- Rad3-related, ATR), which are members of the phosphoinositide tion, replication and repair. The involvement of chromatin 4,5 modifications in transcriptional regulation is relatively well 3-kinase (PI(3)K) superfamily. They catalyse the phosphoryla- characterized, and the distinct patterns of chromatin transitions tion of numerous downstream substrates that are involved in 4,5 that guide the process are thought to be the result of a code on cell-cycle regulation, DNA repair and apoptosis. the histone proteins (histone code). In contrast to transcription, In mammalian cells, DSBs are repaired by one of two distinct the intricate link between chromatin and responses to DNA and complementary pathways – homologous recombination damage has been given attention only recently. It is now (HR) and non-homologous end-joining (NHEJ).6,7 Briefly, NHEJ emerging that specific ATP-dependent chromatin remodeling involves processing of the broken DNA terminii to make them complexes (including the Ino80, Swi/Snf and RSC remodelers) 3 and certain constitutive (methylation of lysine 79 of histone H3) compatible, followed by a ligation step. The core components and DNA damage-induced covalent histone modifications of NHEJ are the Ku70/Ku80 heterodimer, which binds the (the most well characterized being the rapid phosphorylation broken DNA ends, DNA-dependent protein kinase catalytic of histone H2A) facilitate responses to double-strand breaks. subunit (DNA-PKcs), a PI(3)K member that activates and forms a Indeed, evidence is already accumulating for a DNA repair- complex with the nuclease Artemis, and the XRCC4/DNA ligase specific histone code. In this review, the recent advances in 3 our understanding of the relationship between chromatin IV complex, which ligates the processed DNA terminii. modifications and double-strand break signaling and repair Recently, Cernunnos-XLF, a protein that is defective in a rare is discussed. inherited human syndrome characterized by severe immuno- Leukemia (2007) 21, 195–200. doi:10.1038/sj.leu.2404478; deficiency, developmental delay and hypersensitivity to agents published online 7 December 2006 that cause DSBs, has been found to be implicated in NHEJ.8,9 It Keywords: double-strand break; chromatin modification; histone is thought that Cernunnos-XLF interacts with the XRCC4/DNA acetylation; histone phosphorylation; histone methylation; chromatin- 8,9 remodeling complex ligase IV complex. Owing to nucleolytic processing, the NHEJ pathway usually results in the loss of a few nucleotides at each broken end and is typically error-prone. The HR pathway relies on extensive sequence homology between the recombining ends and essentially involves copying Introduction the missing information from an undamaged homologous chromosome.1,2 In contrast to NHEJ, it is typically error-free DNA double-strand breaks (DSBs), which can arise from normal and is the pathway that is predominantly used by the simple (e.g. V(D)J and meiotic recombination) and pathological (stalled eucaryotes such as the yeasts Saccharomyces cerevisiae and replication forks and reactive oxygen species) endogenous Schizosaccharomyces pombe to repair DSBs.1,2 Genetic ana- metabolic processes or from exogenous agents (e.g. ionizing lysis of S. cerevisiae indicated that proteins coded by the RAD52 radiation and radiomimetic drugs), are the most severe lesions epistasis group of genes – RAD50, RAD51, RAD52, RAD54, with respect to cell survival and preservation of genomic RAD55, RAD57, RAD59, MRE11 and XRS2 – are important in integrity.1,2 Therefore, cells have evolved complex mechanisms HR.1,2,10 Sequentially, the HR repair process that involves the that include cell cycle arrest, activation and increased expres- generation of a single-stranded region of DNA by a process sion of various genes including those associated with DNA which involves nucleolytic resection by the Mre11–Rad50–Xrs2 repair and in certain cases induction of the apoptotic pathway, (MRE11-RAD50-NBS1(nibrin) in mammalian cells) complex, to respond to DSBs.1–3 The overall cellular response to DSBs has strand invasion mediated by the replication protein A (RPA)- been considered as a classical signal-transduction cascade coated Rad51 nucleoprotein filament, formation of a Holliday where the lesions (signals) are detected by sensor proteins that junction, DNA synthesis by polymerases, branch migration and activate protein kinase (transduction) cascades, which result in resolution.7 Studies have identified that mammalian homologs amplification and diversification of the signal through a series of exist for all known gene products involved in yeast HR, downstream effector molecules (response).1,2 The central DSB indicating that the basic HR pathway is conserved in higher signaling kinases in mammalian cells are ataxia telangiectasia eucaryotes.11–13 Common sense dictates that the molecular responses to DBSs Correspondence: Dr A El-Osta, Epigenetics in Human Health and must occur within the constraints of chromatin. In eucaryotic Disease Laboratory, Baker Medical Research Institute, The Alfred cells, the primary repeating unit of chromatin is the nucleosome, Medical Research and Education Precinct (AMREP), Second Floor, a nucleoprotein complex that consists of DNA wrapped around Commercial Road, Prahran, Victoria 3181, Australia. an octameric structure, which is constructed by two copies of E-mail: [email protected] 14,15 Received 10 October 2006; accepted 18 October 2006; published each of the four core histones, H2A, H2B, H3 and H4. online 7 December 2006 Strings of thousands of nucleosomes are organized onto a Chromatin modifications and DSB response TC Karagiannis and A El-Osta 196 continuous DNA helix (typically separated by 10–60 base pairs catalytically active monomers (a radiation dose of 0.5 Gy, of linker DNA).16 Nucleosomes are further compacted into which induces about 18 DSBs, resulted in the phosphorylation 30 nm chromatin fibers via linker histones (H1) and looped of approximately 50% of ATM molecules within 5 min) may be domains and these are assembled into so-called higher order due to changes in chromatin structure and/or histone modifica- chromatin structures that are not well defined.16 Although tions, which are detected by ATM.21 This model is supported by nucleosomes have been traditionally known simply as stable the findings from a very recent report in which changes in DNA packaging units, it is now evident that they are dynamic chromatin structure following DSB induction were monitored.22 structures that can be altered by at least three different The findings indicated that chromatin undergoes an energy- processes. The composition of nucleosomes may be modified dependent local expansion immediately following the induction by the incorporation of histone variants, which are thought to of DSBs.22 It was found that the conformational change in have specialized functions.17 Additionally, the organization of chromatin occurs independently of ATM and g-H2AX (discussed chromatin can be altered by the replacement, repositioning or in below).22 Furthermore, in support of the initial ATM autopho- certain cases the ejection of nucleosomes by ATP-dependent sphorylation hypothesis,21 the data demonstrate that local chromatin remodeling complexes.18 Finally, chromatin struc- activation of ATM occurs with the same spatio-temporal ture can be modified by coordinated post-translational mod- dynamics as the changes in chromatin architecture.22 For a ifications on histone residues such as acetylation of lysines, balanced perspective, it should be noted that other recent serine phosphorylation, methylation of lysines and arginines, observations may question some aspects of the chromatin polyribosylation and ubiquitylation.19,20 It is not unexpected modification-induced ATM autophosphorylation model. The that numerous studies have begun to demonstrate that specific ATP-dependent chromatin remodeling complexes and certain constitutive and DNA damage-induced covalent histone mod- ifications facilitate the DNA-damage response. The remaining of the article will focus on the relationships between chromatin modifications and DSB signaling and repair that have been identified to date (Figure 1). Recognition of double-strand breaks The findings from a landmark study provided evidence for a link between changes in chromatin conformation and the initial detection of DSBs.21 The results from the study indicated that in response to genotoxic stress, inactive homodimeric or multi- meric ATM molecules are modified by autophosphorylation of the serine-1891 residue resulting in activation of the ATM protein kinase domain.21 It was rationalized that the rapid and widespread dissociation of inactive ATM complexes into Figure 1 Key
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