ReviewInterplay between chromatin and cell cycle checkpoints in the context of ATR/ATM-dependent checkpoints
Introduction
In eukaryotic cells, nuclear DNA is compacted with proteins in the form of chromatin [1], the basic unit of which is the nucleosome core, comprising 146 base-pairs of DNA wrapped around a histone octamer [2], [3]. This basic unit contains four core histones, highly basic proteins that can be subjected to various covalent post-translational modifications, such as acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation [4], [5]. From their site of synthesis up to their delivery point, they are escorted by histone chaperones, among which the best known to date are involved in histone deposition to facilitate nucleosome formation [6], [7]. Genetic alterations as well as abnormal expression of histones, histone modifiers, or histone chaperones, including chromatin assembly factors, may thus result in aberrant situations such as defects in chromatin organization. Given that chromatin is intimately involved in many DNA transactions, including transcription, replication, repair and recombination, any event impairing the stability of chromatin structure is likely to compromise DNA metabolism and genome integrity. Defects that can lead to chromatin abnormalities should thus be detected and chromatin structure restored in order to ensure conservation of both genome integrity and its functional organization.
Maintenance of genomic integrity is a major challenge for cells, which are continuously exposed to genotoxic stress. Eukaryotic cells have thus evolved cell cycle checkpoint mechanisms that are surveillance pathways to detect DNA breaks, replication arrest, or defects in mitotic spindle assembly. The checkpoint concept was initially formulated in terms of a genetically controlled dependency between ordered cell cycle events, the initiation of late processes depending upon the completion of early ones [8]. Acting both during normal cell growth and under perturbed conditions, these checkpoint pathways trigger cell cycle arrest in Gl/S, S, G2/M or M, providing additional time for repair, or leading to apoptosis [9], [10], [11]. Conserved kinases acting as upstream regulators in the signalling checkpoint cascade during Gl/S, intra S and G2/M, known as the Ataxia Telangiectasia Mutated (ATM) and ATM-Related (ATR) family [12], [13] in mammals and Mecl/Tell in yeast Saccharomyces cerevisiae, have helped unveil several potential links with chromatin dynamics. ATM is considered as a primary regulator in response to DNA double strand breaks (DSBs) [14], whereas ATR has been implicated primarily in the response to ultraviolet light (UV), replication blocks and hypoxia. One should stress, however, that the signal eliciting the checkpoint response is not necessarily a direct detection of the primary damage. In many instances, it could involve recognition of processed intermediates [9], or perhaps detection of a modified chromatin structure. Indeed, recent data indicate that checkpoint pathways are not necessarily activated only by DNA lesions but may also respond to chromatin structure abnormalities, highlighting the importance of considering checkpoint responses in the context of chromatin.
In this review, we will present evidence of an interplay between chromatin organization and ATM/ATR-dependent checkpoints. Chromatin-based events appear to be linked to the checkpoint response in two ways, that are not mutually exclusive: (i) they can be involved upstream as initiators of the checkpoint pathway, (ii) they can act downstream as effectors, contributing to a more efficient repair process both at the DNA and the chromatin levels, or perhaps even for the choice to enter into apoptosis (Fig. 1).
Section snippets
Chromatin-based events as a trigger of cell cycle checkpoints
The functional organization of the genome can be affected by various damaging agents: (i) of both endogenous and exogenous origin (chemical, radiations), (ii) occurring during DNA metabolism (intrinsic perturbation: stalled replication, mismatch). Chromatin defects that ensue may serve as an initiating signal for the activation of cell cycle checkpoints. In addition, DNA lesions may be concomitantly induced and participate in checkpoint activation.
Cell cycle checkpoints modulate chromatin organization
There is evidence that repair processes can involve important modifications in chromatin organization. An “access-repair-restore” model has thus been proposed in the context of nucleotide excision repair (NER) [42] and could be further extended to other repair processes. According to this model, modulations of chromatin structure allow the access of the repair machinery to DNA damage and chromatin structure is subsequently restored once the repair process is complete. The “access” step involves
Conclusions and perspectives
The recent data presented here are changing our view about checkpoint responses. Considered mainly as DNA-based signalling transduction pathways, they have to integrate a chromatin-based dimension, which may be equally important, at each step of the cascade of events (Fig. 1): upstream, to participate in signalling the defects or downstream, to contribute to a more efficient repair process. If chromatin-based defects are indeed acting as initiators of the checkpoint pathway, this supposes an
Acknowledgements
We thank P. Hanawalt, A. Groth and P.A. Defossez for critical reading of the manuscript. G.A. is supported by la Ligue Nationale contre le Cancer (Equipe labellisée la Ligue), Euratom (FIGH-CT-1999-00010, FIGH-CT-2002-00207), the Commissariat à l’Energie Atomique (LCR no. 26) European Contracts RTN (HPRN-CT-2000-00078 and HPRN-CT-2002-00238) and Collaborative Programme between the Curie Institute and the Commissariat à l’Energie Atomique (PIC Paramètres Epigénétiques).
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2015, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :Laboratory studies have provided evidence that eukaryotic cells respond to radiation damage by activating DNA-damage response (DDR) pathways through which signal transduction processes alert the cell to the presence of DNA damage and trigger such downstream events as cell cycle arrest, repair and apoptosis (reviewed in [66–69]). The critical components that are activated by DSBs include the MRE11-RAD50-NBS1 complex (MRN complex; also involved in the homologous recombination repair [HRR] pathway); Ku proteins and phosphatidylinositol 3-kinase-related kinases (PIKK); DNA-PKcs; the ATM (ataxia-telangiectasia mutated) protein kinase and the ATR (ataxia-telangiectasia-related) kinase [also involved in the NHEJ pathway] [70–78]. Another early step in the response of the cell to DSBs is the triggering of phosphorylation of the H2A histone family,9 member X, H2AX, which can be carried out redundantly by ATM or DNA-dependent protein kinase (DNA-PKcs)[79].
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These authors contributed equally to this work.