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Review
. 2021 Sep 1:12:730696.
doi: 10.3389/fgene.2021.730696. eCollection 2021.

DNA Double-Strand Break Repair: All Roads Lead to HeterochROMAtin Marks

Pierre Caron  1 , Enrico Pobega  1 , Sophie E Polo  1
Affiliations
Review

DNA Double-Strand Break Repair: All Roads Lead to HeterochROMAtin Marks

Pierre Caron et al. Front Genet. .

Abstract

In response to DNA double-strand breaks (DSBs), chromatin modifications orchestrate DNA repair pathways thus safeguarding genome integrity. Recent studies have uncovered a key role for heterochromatin marks and associated factors in shaping DSB repair within the nucleus. In this review, we present our current knowledge of the interplay between heterochromatin marks and DSB repair. We discuss the impact of heterochromatin features, either pre-existing in heterochromatin domains or de novo established in euchromatin, on DSB repair pathway choice. We emphasize how heterochromatin decompaction and mobility further support DSB repair, focusing on recent mechanistic insights into these processes. Finally, we speculate about potential molecular players involved in the maintenance or the erasure of heterochromatin marks following DSB repair, and their implications for restoring epigenome function and integrity.

Keywords: DNA double-strand break repair pathway choice; chromatin mobility; chromatin remodeling factors; heterochromatin; histone modifications; histone variants.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Heterochromatin features govern DNA double-strand break (DSB) repair pathway choice. Representation of heterochromatic (HC) histone modifications, histone variants, and non-histone chromatin factors that modulate DSB repair pathway choice in mammalian cells. Features that favor homologous recombination (HR), non-homologous end joining (NHEJ), and microhomology-mediated end joining (MMEJ) are shown in green, yellow, and blue, respectively. The types of heterochromatin enriched in these features are indicated when known. The contribution of centromeric histone variant and modifications to promoting HR in G1 is still to be determined, as indicated by the question marks.
Figure 2
Figure 2
Cytoskeleton factors regulate the mobility of damaged heterochromatin to support DSB repair. Nucleoskeleton factors and molecular motors (shown in red in the center circle) are involved in the mobility of heterochromatic DSBs (DSB mobility is represented by red arrows in the peripheral circles). Chromatin mobility is further supported by microtubules, which provide mechanical forces. This process is conserved in several species and promotes the repair of DSBs occurring within different heterochromatin compartments. DSB repair pathways operating in each case are indicated.
Figure 3
Figure 3
Heterochromatin features are transiently established following DSBs. Following DSB induction, the chromatin surrounding the lesion is modified by the deposition of heterochromatin-specific histone variants and post-translational modifications (red) at the expense of active marks (green). This contributes to silence transcription in the vicinity of the DSB. For simplicity, all chromatin marks are represented on a single nucleosome flanking a DSB. Most of the players that promote the recovery of the pre-existing marks after completion of DSB repair are still unknown, as indicated by the question marks. White ovals and rectangles represent histone modifying enzymes and histone chaperone/remodeler, respectively.
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