Chromatin dynamics after DNA damage: The legacy of the access-repair-restore model (original) (raw)
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Chromatin structure and DNA damage repair
Epigenetics & Chromatin, 2008
The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. These damaging agents can induce a wide variety of lesions in the DNA, such as double strand breaks, single strand breaks, oxidative lesions and pyrimidine dimers. The cell has evolved intricate DNA damage response mechanisms to counteract the genotoxic effects of these lesions. The two main features of the DNA damage response mechanisms are cell-cycle checkpoint activation and, at the heart of the response, DNA repair. For both damage signalling and repair, chromatin remodelling is most likely a prerequisite. Here, we discuss current knowledge on chromatin remodelling with respect to the cellular response to DNA damage, with emphasis on the response to lesions resolved by nucleotide excision repair. We will discuss the role of histone modifications as well as their displacement or exchange in nucleotide excision repair and make a comparison with their requirement in transcription and double strand break repair.
When repair meets chromatin: First in series on chromatin dynamics
EMBO Reports, 2002
In eukaryotic cells, the inheritance of both the DNA sequence and its organization into chromatin is critical to maintain genome stability. This maintenance is challenged by DNA damage. To fully understand how the cell can tolerate genotoxic stress, it is necessary to integrate knowledge of the nature of DNA damage, its detection and its repair within the chromatin environment of a eukaryotic nucleus. The multiplicity of the DNA damage and repair processes, as well as the complex nature of chromatin, have made this issue difficult to tackle. Recent progress in each of these areas enables us to address, both at a molecular and a cellular level, the importance of interrelationships between them. In this review we revisit the 'access, repair, restore' model, which was proposed to explain how the conserved process of nucleotide excision repair operates within chromatin. Recent studies have identified factors potentially involved in this process and permit refinement of the basic model. Drawing on this model, the chromatin alterations likely to be required during other processes of DNA damage repair, particularly double-strand break repair, are discussed and recently identified candidates that might perform such alterations are highlighted.
ATP-dependent chromatin remodeling in the DNA-damage response
Epigenetics & Chromatin, 2012
The integrity of DNA is continuously challenged by metabolism-derived and environmental genotoxic agents that cause a variety of DNA lesions, including base alterations and breaks. DNA damage interferes with vital processes such as transcription and replication, and if not repaired properly, can ultimately lead to premature aging and cancer. Multiple DNA pathways signaling for DNA repair and DNA damage collectively safeguard the integrity of DNA. Chromatin plays a pivotal role in regulating DNA-associated processes, and is itself subject to regulation by the DNA-damage response. Chromatin influences access to DNA, and often serves as a docking or signaling site for repair and signaling proteins. Its structure can be adapted by post-translational histone modifications and nucleosome remodeling, catalyzed by the activity of ATP-dependent chromatin-remodeling complexes. In recent years, accumulating evidence has suggested that ATP-dependent chromatin-remodeling complexes play important, although poorly characterized, roles in facilitating the effectiveness of the DNA-damage response. In this review, we summarize the current knowledge on the involvement of ATP-dependent chromatin remodeling in three major DNA repair pathways: nucleotide excision repair, homologous recombination, and non-homologous end-joining. This shows that a surprisingly large number of different remodeling complexes display pleiotropic functions during different stages of the DNA-damage response. Moreover, several complexes seem to have multiple functions, and are implicated in various mechanistically distinct repair pathways.
International journal of molecular sciences, 2017
Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote access of relevant enzymes to specific DNA regions for signaling and repair. Furthermore, recent data highlight genome maintenance roles of chromatin through the regulation of endogenous DNA-templated processes including transcription and replication. Here, we review research that shows the importance of chromatin structure regulation in maintaining genome integrity by multiple mechanisms including facilitating DNA repair and directly suppressing endogenous DNA damage.
Chromatin and the DNA damage response: The cancer connection
Molecular Oncology, 2011
The integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management. Attikum). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / m o l o n c 1574-7891/$ e see front matter ยช
Function of chromatin structure and dynamics in DNA damage,repair and misrepair
2011
The majority of DSBs are repaired individually close to the sites of their origin. c Decondensation of damaged chromatin domains can potentiate clustering of lesions. c DSB clustering might increase the risk of chromatin translocation. c Distances of lesions and higher-order chromatin structure influence DSB clustering. c The conclusions seem to hold both for DSB damage caused by g-radiation and protons.
Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates
Nature Structural & Molecular Biology, 2017
Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated. Here we show that cellular levels of histones drop 20-40% in response to DNA damage. This histoneloss occurs from chromatin, is proteasome mediated and requires both the DNA damage checkpoint and INO80 nucleosome remodeler. Histone level reduction was confirmed by SILAC-based mass spectroscopy, genome-wide nucleosome mapping and fluorescence microscopy. Chromatin decompaction and increased fiber flexibility accompany histone degradation, both in response to DNA damage and upon artificially reducing histone levels. As a result, recombination rates and DNA repair focus turnover are enhanced. Thus, we propose that a generalized reduction in nucleosome occupancy is an integral part of the DNA damage response, providing mechanisms for enhanced chromatin mobility and homology search.
Nucleus (Austin, Tex.)
During transcription, RNA polymerase may encounter DNA lesions, which causes stalling of transcription. To overcome the RNA polymerase blocking lesions, the transcribed strand is repaired by a dedicated repair mechanism, called transcription coupled nucleotide excision repair (TC-NER). After repair is completed, it is essential that transcription restarts. So far, the regulation and exact molecular mechanism of this transcriptional restart upon genotoxic damage has remained elusive. Recently, three different chromatin remodeling factors, HIRA, FACT, and Dot1L, were identified to stimulate transcription restart after DNA damage. These factors either incorporate new histones or establish specific chromatin marks that will gear up the chromatin to subsequently promote transcription recovery. This adds a new layer to the current model of chromatin remodeling necessary for repair and indicates that this specific form of transcription, i.e., the transcriptional restart upon DNA damage, ne...
Function of Chromatin Structure and Dynamics in DNA Damage, Repair and Misrepair; in press
2012
The majority of DSBs are repaired individually close to the sites of their origin. c Decondensation of damaged chromatin domains can potentiate clustering of lesions. c DSB clustering might increase the risk of chromatin translocation. c Distances of lesions and higher-order chromatin structure influence DSB clustering. c The conclusions seem to hold both for DSB damage caused by g-radiation and protons.
Nucleosome dynamics as modular systems that integrate DNA damage and repair
Cold Spring Harbor perspectives in biology, 2013
By some estimates, a eukaryotic cell must repair up to 10,000 DNA lesions per cell cycle to counteract endogenous sources of DNA damage. Exposure to environmental toxins, UV sources, or other radiations only increases this enormous number. Failure to repair such lesions can lead to a deleterious mutation rate, genomic instability, or cell death. The timely and efficient repair of eukaryotic DNA damage is further complicated by the realization that DNA lesions must be detected and repaired in the context of chromatin with its complex organization within the nucleus. Numerous studies have shown that chromatin packaging can inhibit nearly all repair pathways, and recent work has defined specific mechanisms that facilitate DNA repair within the chromatin context. In this review, we provide a broad overview of chromatin regulatory mechanisms, mainly at the nucleosomal level, and then focus on recent work that elucidates the role of chromatin structure in regulating the timely and efficie...