Key Points
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Three pathways for maintaining genomic integrity are influenced by chromatin: DNA damage repair, DNA replication and chromosome segregation.
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At DNA double-strand breaks (DSBs), only limited chromatin structure alterations have been defined. Nucleosomes do not appear to be completely lost from DSB ends, even following extensive end processing.
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A subset of histone post-translational modifications may control the efficiency of DNA repair as well as the cell cycle checkpoint by regulating chromatin higher-order structure
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Induction of a chromosomal DSB can enhance the nuclear mobility of chromatin, and this appears to play a key part in the repair of euchromatic DSBs in yeast and heterochromatic DSBs in Drosophila melanogaster. Enhanced chromosome mobility may require the action of ATP-dependent chromatin-remodelling enzymes.
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Histone post-translational modifications and histone variants create a complex signalling platform that controls the robustness of the cell cycle checkpoint response and appears also to integrate the DDR pathway with other cellular events.
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Chromatin-remodelling enzymes appear to have complex roles in facilitating DNA replication through chromatin structures and stabilizing the replisome. Currently, however, mechanistic studies are limiting our understanding.
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Histone post-translational modifications can regulate the binding of non-histone proteins to kinetochores, regulating chromosome segregation. Chromatin-remodelling enzymes can control the distribution of centromere-specific histone variants and appear to have other undefined roles in the fidelity of chromosome segregation.
Abstract
The maintenance of genome integrity is essential for organism survival and for the inheritance of traits to offspring. Genomic instability is caused by DNA damage, aberrant DNA replication or uncoordinated cell division, which can lead to chromosomal aberrations and gene mutations. Recently, chromatin regulators that shape the epigenetic landscape have emerged as potential gatekeepers and signalling coordinators for the maintenance of genome integrity. Here, we review chromatin functions during the two major pathways that control genome integrity: namely, repair of DNA damage and DNA replication. We also discuss recent evidence that suggests a novel role for chromatin-remodelling factors in chromosome segregation and in the prevention of aneuploidy.
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Acknowledgements
We thank L. Prendergast and members of the Peterson laboratory for helpful comments and discussion.
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Supplemental information S1 (table)
Chromatin regulatory factors functionally or physically associated with genome stability pathways. Note: '/?' in row 3 means 'another unknown in vivo function' (PDF 397 kb)
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Glossary
- Holliday junction
-
An intermediate in homologous recombination comprised of four DNA strands.
- V(D)J recombination
-
A somatic recombination event in lymphoid cells in which different variable, diverse and joining gene segments are combined as a part of the process to form diverse immunoglobulins and T cell receptors.
- Resection
-
Exonucleolytic processing of the 5′ DNA strand at double-strand breaks, resulting in a 3 ssDNA 'tail'.
- DNA base adducts
-
DNA bases that contain a covalently bound chemical, often induced by cellular exposure to carcinogens.
- Translesion synthesis
-
(TLS). A DNA tolerance pathway that allows replication to proceed through DNA lesions. This pathway involves fork-associated switching of a normal polymerase for a specialized translesion polymerase.
- Chromosomal instability
-
(CIN). A cellular phenotype characterized by high rates of chromosome mis-segregation, leading to loss or gain of whole chromosomes.
- Cytokinesis
-
A late stage of mitosis in which a cell divides to form two daughter cells
- Midbody
-
A transient structure found in mammalian cells that connects two daughter cells at the end of cytokinesis. The midbody is important for the final abscission (cleavage) event.
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Papamichos-Chronakis, M., Peterson, C. Chromatin and the genome integrity network. Nat Rev Genet 14, 62–75 (2013). https://doi.org/10.1038/nrg3345
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DOI: https://doi.org/10.1038/nrg3345
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