The Sound of Silence: How Silenced Chromatin Orchestrates the Repair of Double-Strand Breaks

Abstract

The eukaryotic nucleus is continuously being exposed to endogenous and exogenous sources that cause DNA breaks, whose faithful repair requires the activity of dedicated nuclear machineries. DNA is packaged into a variety of chromatin domains, each characterized by specific molecular properties that regulate gene expression and help maintain nuclear structure. These different chromatin environments each demand a tailored response to DNA damage. Silenced chromatin domains in particular present a major challenge to the cell’s DNA repair machinery due to their specific biophysical properties and distinct, often repetitive, DNA content. To this end, we here discuss the interplay between silenced chromatin domains and DNA damage repair, specifically double-strand breaks, and how these processes help maintain genome stability.

DNA Double-Strand Break Movement in Heterochromatin Depends on the Histone Acetyltransferase dGcn5

“…Overall, our results provide an exciting illustration of how heterochromatin uniquely responds to a DSB, and modifies its chromatin features to promote successful repair. This is in line with the idea that chromatin components and chromatin-associated factors actively participate in the process of DSB repair and are fine-tuned depending on the respective chromatin domain 22,37,66 . Future research into how diverse chromatin environments affect and regulate the response to DSBs therefore represents a critical goal in order to understand not only how genomic stability is maintained across the eukaryotic nucleus, but also how failure to maintain genomic integrity can result in disease development.…”

The intrinsically disordered region of the E3 ubiquitin ligase TRIP12 induces the formation of chromatin condensates and interferes with DNA damage response

“…The efficiency of the DDR greatly depends on chromatin compaction. Nuclear F-actin and myosin drive the re-localization of heterochromatic breaks in relaxed chromatin 50 . Up to now, TRIP12 has been implicated in the inhibition of NHEJ and Alternative End joining (Alt-EJ) DDR pathways via the action of its HECT catalytic domain by inducing the ubiquitination of RNF168 and PARP1, respectively 4,5 .…”

An Expanding Toolkit for Heterochromatin Repair Studies

“…[ 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]). Pericentromeric repeats are also distinct from Polycomb-mediated silenced regions, which are typically enriched for H3K27me3 and encompass LADs and other silenced domains [ 16 ] (reviewed in [ 17 , 18 ]). Pericentromeric heterochromatin is absent in budding yeast; thus, repair in these sequences has mostly been studied in Drosophila , mouse, and human cells.…”

“…The Y chromosome is mostly heterochromatin. ( B ) Position of pericentromeric heterochromatin relative to the nuclear periphery in a Drosophila nucleus, which is distinct from LADs, telomeric repeats, and Polycomb-repressed domains (adapted from [ 7 , 18 ]).…”

“…Various techniques have been developed to study DSB repair, as recently reviewed [ 34 ]. Specific approaches have also been applied to the study of DSB repair in other ‘silent’ genomic regions, such as telomeres [ 35 ], LADs [ 36 ], Polycomb-rich regions [ 37 , 38 ], other silenced repeats [ 39 ], and untranscribed loci (inactive genes or intergenic regions) [ 40 ] (reviewed in [ 18 ]). Additional studies have characterized the responses in pericentromeric regions to damage other than DSBs, such as from UV exposure [ 41 ], and heterochromatin replication or over-replication [ 42 , 43 ], and will not be covered by this review.…”