Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 62 (5), 712-27

Epigenome Maintenance in Response to DNA Damage

Affiliations
Review

Epigenome Maintenance in Response to DNA Damage

Juliette Dabin et al. Mol Cell.

Abstract

Organism viability relies on the stable maintenance of specific chromatin landscapes, established during development, that shape cell functions and identities by driving distinct gene expression programs. Yet epigenome maintenance is challenged during transcription, replication, and repair of DNA damage, all of which elicit dynamic changes in chromatin organization. Here, we review recent advances that have shed light on the specialized mechanisms contributing to the restoration of epigenome structure and function after DNA damage in the mammalian cell nucleus. By drawing a parallel with epigenome maintenance during replication, we explore emerging concepts and highlight open issues in this rapidly growing field. In particular, we present our current knowledge of molecular players that support the coordinated maintenance of genome and epigenome integrity in response to DNA damage, and we highlight how nuclear organization impacts genome stability. Finally, we discuss possible functional implications of epigenome plasticity in response to genotoxic stress.

Figures

Figure 1
Figure 1. Epigenome maintenance in mammalian cells: parallel between replication and repair.
DNA repair (A) and replication (B) involve similar chromatin dynamics with shared histone chaperones (yellow) promoting the mobilization of parental histones (red) and the deposition of newly synthesized histones (green). For simplicity, shared chromatin remodeling complexes are not represented. Both at the replication fork and at UV damage repair sites, new H3.1 deposition by CAF-1 is coupled to DNA synthesis while new H3.3 histones are deposited by HIRA independently of DNA synthesis. The histone chaperone FACT also promotes histone dynamics in response to UVC damage while ASF1 and Nucleolin are involved in the response to DSBs. Subsequent chromatin maturation involves erasure of naive histone marks (green), transmission of parental histone marks (red) to newly synthesized histones, and maintenance of DNA methylation (black). Although such processes have been described at the replication fork, related mechanisms at repair sites are still to be characterized. Repair and replication factors are represented in blue.
Figure 2
Figure 2. Coordination between genome and epigenome maintenance in response to DNA damage.
The coordinated maintenance of genome integrity and epigenome stability along the repair process in mammalian cells is supported by direct molecular interactions of DDR factors (blue) with histone modifications (P: phosphorylation; Ub: ubiquitination; Me: methylation), histone chaperones (yellow) and the DNA methylation machinery (black). DNA damage signaling factors: ATM: Ataxia Telangiectasia Mutated; MDC1: Mediator of DNA damage Checkpoint 1; RNF: RING Finger protein; MMSET: Multiple Myeloma SET domain; 53BP1: TP53 Binding Protein 1.
Figure 3
Figure 3. Impact of nuclear organization on genome maintenance in response to DNA damage in mammalian cells
(A) The spatial proximity of chromosome territories in the mammalian cell nucleus determines partner selection in chromosome translocations. Chromosome breakpoints (blue stars) are characterized by an enrichment in the transcription-associated histone mark H3K4me3, which facilitates DSB formation. (B) Nuclear position of DSBs (blue stars) dictates repair pathway choice. NHEJ: non-homologous end-joing, A-EJ: alternative end joining, HR: homologous recombination. DSBs located in actively transcribed genes are targeted to HR repair via the transcription elongation–associated histone mark H3K36me3. (C) Highly compact heterochromatin domains pose a barrier to repair of DNA damage (blue star). HR: homologous recombination, NER: nucleotide excision repair.
Figure 4
Figure 4. Epigenome integrity vs. plasticity in response to DNA damage in mammalian cells
DNA damage (blue star) elicits substantial chromatin rearrangements, with a loss of parental information (red) due to the mobilization of pre-existing histones, and the incorporation of new information with histone variant exchange and deposition of newly synthesized histones (green), DNA damage-responsive PTMs (blue) and DNA methylation (black). For simplicity, factors escorting and mobilizing histones and modifying enzymes for histones and DNA are not represented. Future challenges in the field will be to determine whether or not the pre-existing chromatin landscape is ultimately faithfully restored after genotoxic stress, thus allowing the maintenance of epigenome integrity. Alternatively, the persistence of a damage scar on chromatin (dotted line box) could contribute to damage memory, maintenance of stem cell identity or reprogramming.

Similar articles

See all similar articles

Cited by 26 PubMed Central articles

See all "Cited by" articles

References

    1. Adam S, Polo SE. Blurring the line between the DNA damage response and transcription: the importance of chromatin dynamics. Exp Cell Res. 2014;329:148–153. - PMC - PubMed
    1. Adam S, Dabin J, Polo SE. Chromatin plasticity in response to DNA damage: The shape of things to come. DNA Repair (Amst.) 2015a;32:120–126. - PMC - PubMed
    1. Adam S, Dabin J, Bai S-K, Polo SE. Imaging Local Deposition of Newly Synthesized Histones in UVC-Damaged Chromatin. Methods Mol Biol. 2015b;1288:337–347. - PubMed
    1. Adam S, Polo SE, Almouzni G. Transcription Recovery after DNA Damage Requires Chromatin Priming by the H3.3 Histone Chaperone HIRA. Cell. 2013;155:94–106. - PubMed
    1. Agmon N, Liefshitz B, Zimmer C, Fabre E, Kupiec M. Effect of nuclear architecture on the efficiency of double-strand break repair. Nat Cell Biol. 2013;15:694–699. - PubMed

Publication types

MeSH terms

LinkOut - more resources

Feedback