Review
doi: 10.1101/gad.307702.117.Chromatin and nucleosome dynamics in DNA damage and repair
Affiliations
- PMID:29284710
- PMCID: PMC5769766
- DOI: 10.1101/gad.307702.117
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Review
Chromatin and nucleosome dynamics in DNA damage and repair
Michael H Hauer et al. Genes Dev..
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Abstract
Chromatin is organized into higher-order structures that form subcompartments in interphase nuclei. Different categories of specialized enzymes act on chromatin and regulate its compaction and biophysical characteristics in response to physiological conditions. We present an overview of the function of chromatin structure and its dynamic changes in response to genotoxic stress, focusing on both subnuclear organization and the physical mobility of DNA. We review the requirements and mechanisms that cause chromatin relocation, enhanced mobility, and chromatin unfolding as a consequence of genotoxic lesions. An intriguing link has been established recently between enhanced chromatin dynamics and histone loss.
Keywords: DNA damage; chromatin structure; histones; nuclear organization; nucleosome remodelers.
© 2017 Hauer and Gasser; Published by Cold Spring Harbor Laboratory Press.
Figures
Chromatin structure and function. Nucleosomes consist of octameric histone complexes and come in many different “flavors” owing to a multitude of histone variants and histone tail modifications. Both cytosolic and nuclear chaperones protect newly synthesized histones and assemble them into nucleosomes. The abundant high-mobility group proteins bind DNA and chromatin, altering nucleosome stability. In themiddle panel, we show how chromatin remodeling complexes organize nucleosomes along DNA through ATP-dependent reactions. Actin-related proteins dimerize with actin within remodelers and chaperones and may mediate histone contacts. Chromatin folds into higher-order structures. Whole chromosomes assume three-dimensional organization in the nucleus, yet chromatin remains locally mobile. Chromatin interaction with the nuclear envelope and pores as well as with itself leads to subcompartmentation of the yeast nucleus.
Checkpoint activation and DSB repair in the context of chromatin. (A) Proteins involved in DDC activation in response to a DSB. The checkpoint stalls the cell cycle and coordinates repair proteins acting at the site of damage. Mammalian proteins are capitalized. (B) Three of the main DSB repair pathways are shown: NHEJ, single-strand annealing (SSA), and HR (see the text for details). HR intermediates are resolved by subsequent pathways, resulting in different repair outcomes (light-blue box). (BIR) Break-induced replication; (SDSA) synthesis-dependent strand annealing; (dHJ) double-Holliday junction. (C) Effects of both the DDC and the DSB repair functions integrate on the chromatin template. The key steps and the main players during homology-directed DSB repair are listed. The first panel highlights early steps after DSB formation. The second panel illustrates DSB processing and spreading of the DDC signal. The last panel shows the Rad51 nucleofilament before homology search and after strand invasion and repair.
Concepts of local and global chromatin mobility in response to DNA damage. (A) A summary of local DSB mobility events. Formation of a DSB activates the DDC kinase Mec1/ATR, which phosphorylates downstream effector proteins (in yeast, Rad9 and Rad53) as well as chromatin remodeling complexes (INO80-C). If the DSB is repaired by HR, local repair proteins process the lesion, leading to the formation of the Rad51 nucleofilament, which will engage in homology search and recombinational repair. Chromatin locally unfolds at the break site, and histones and other proteins are modified by PARylation, SUMOylation, and ubiquitination. These promote the extrusion of damage from heterochromatic domains and increase access for repair factors. DSBs become more mobile, which is thought to facilitate homology search throughout the nuclear volume and promote relocation events to the nuclear periphery. Both the DDC and chromatin remodelers are needed to enhance DSB mobility. (B) Model for global chromatin mobility. Multiple random DSBs and single-strand breaks cause a global increase in chromatin mobility, which in yeast requires Mec1, Rad53, and INO80-C. Both the checkpoint and INO80-C trigger proteasome-dependent degradation of core histones in response to damage, which decompacts chromatin, enhances global mobility, and facilitates repair. The impact of forced histone reduction is highlighted in blue. (C) Multiple mechanisms contribute to chromatin mobility following DNA damage in yeast. Chromatin expands in response to damage-driven histone degradation. Cytoplasmic actin filaments can enhance nuclear rotation. Potentially, a loss of attachment through events such as centromere release might further increase chromatin mobility.
References
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