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

Caron, Pierre; Pobega, Enrico; Polo, Sophie E.

doi:10.3389/fgene.2021.730696

Cited by 16 publications

(12 citation statements)

References 89 publications

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“…Notably, chromatin marks and histone variants are deposited de novo on DSB-flanking sequences, including typical heterochromatin marks. This, along with variations in the chromatin compaction around DSB, plays a central role in DSB repair pathway choice (for a review see [ 111 ]). Higher-order chromatin folding is also modified, with the strengthening of TAD boundaries [ 112 , 113 ], an enrichment of TAD cliques and the formation of a new interaction-based subcompartment (D compartment) that groups damaged sequences with nondamaged loci enriched in chromatin marks typical of active transcription (H2AZac, H3K4me3 and H3K79me2; [ 113 ]).…”

Section: Genome Folding and Chromatin Dynamics Modulate Dna Repairmentioning

confidence: 99%

DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex

Phipps

Dubrana

2022

Genes

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DNA double-strand breaks (DSBs) are a deleterious form of DNA damage, which must be robustly addressed to ensure genome stability. Defective repair can result in chromosome loss, point mutations, loss of heterozygosity or chromosomal rearrangements, which could lead to oncogenesis or cell death. We explore the requirements for the successful repair of DNA DSBs by non-homologous end joining and homology-directed repair (HDR) mechanisms in relation to genome folding and dynamics. On the occurrence of a DSB, local and global chromatin composition and dynamics, as well as 3D genome organization and break localization within the nuclear space, influence how repair proceeds. The cohesin complex is increasingly implicated as a key regulator of the genome, influencing chromatin composition and dynamics, and crucially genome organization through folding chromosomes by an active loop extrusion mechanism, and maintaining sister chromatid cohesion. Here, we consider how this complex is now emerging as a key player in the DNA damage response, influencing repair pathway choice and efficiency.

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Section: Genome Folding and Chromatin Dynamics Modulate Dna Repairmentioning

confidence: 99%

DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex

Phipps

Dubrana

2022

Genes

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“…DSB repair pathway choice is strongly dependent on the sequence surrounding and structure of the break [ 32 ]. The location of the break in euchromatin versus heterochromatin also plays a role in repair pathway choice (reviewed in [ 46 ]) The Rr3 construct is designed to promote SSA repair, but not all breaks will have the necessary flanking repeats to carry out SSA. Additionally, it is possible that circadian rhythm disruption could increase NHEJ at the expense of a different pathway, such as HRR.…”

Section: Discussionmentioning

confidence: 99%

A Simulated Shift Work Schedule Does Not Increase DNA Double-Strand Break Repair by NHEJ in the Drosophila Rr3 System

Bergerson

Fitzmaurice

Knudtson

et al. 2022

Genes

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Long-term shift work is widely believed to increase the risk of certain cancers, but conflicting findings between studies render this association unclear. Evidence of interplay between the circadian clock, cell cycle regulation, and DNA damage detection machinery suggests the possibility that circadian rhythm disruption consequent to shift work could alter the DNA double-strand break (DSB) repair pathway usage to favor mutagenic non-homologous end-joining (NHEJ) repair. To test this hypothesis, we compared relative usage of NHEJ and single-strand annealing (SSA) repair of a complementary ended chromosomal double-stranded break using the Repair Reporter 3 (Rr3) system in Drosophila between flies reared on 12:12 and 8:8 (simulated shift work) light:dark schedules. Actimetric analysis showed that the 8:8 light:dark schedule effectively disrupted the rhythms in locomotor output. Inaccurate NHEJ repair was not a frequent outcome in this system overall, and no significant difference was seen in the usage of NHEJ or SSA repair between the control and simulated shift work schedules. We conclude that this circadian disruption regimen does not alter the usage of mutagenic NHEJ DSB repair in the Drosophila male pre-meiotic germline, in the context of the Rr3 system.

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“…In addition to the development of new reporters, genome editing tools will facilitate targeted integration of reporter constructs. This will allow for comparison of repair pathway usage between genomic loci, for example, in hetero- and euchromatic regions, which is an active area of investigation ( Caron et al, 2021 ; Schep et al, 2021 ). Interestingly, Cas9-based tools have been developed to modify the chromatin at target loci ( Goell and Hilton, 2021 ).…”

Section: Future Developments Of Dsb-repair Reportersmentioning

confidence: 99%

Genomic Reporter Constructs to Monitor Pathway-Specific Repair of DNA Double-Strand Breaks

Kooij

Attikum

2022

Front. Genet.

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Repair of DNA Double-Strand Breaks (DSBs) can be error-free or highly mutagenic, depending on which of multiple mechanistically distinct pathways repairs the break. Hence, DSB-repair pathway choice directly affects genome integrity, and it is therefore of interest to understand the parameters that direct repair towards a specific pathway. This has been intensively studied using genomic reporter constructs, in which repair of a site-specific DSB by the pathway of interest generates a quantifiable phenotype, generally the expression of a fluorescent protein. The current developments in genome editing with targetable nucleases like Cas9 have increased reporter usage and accelerated the generation of novel reporter constructs. Considering these recent advances, this review will discuss and compare the available DSB-repair pathway reporters, provide essential considerations to guide reporter choice, and give an outlook on potential future developments.

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

Cited by 16 publications

References 89 publications

DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex

DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex

A Simulated Shift Work Schedule Does Not Increase DNA Double-Strand Break Repair by NHEJ in the Drosophila Rr3 System

Genomic Reporter Constructs to Monitor Pathway-Specific Repair of DNA Double-Strand Breaks

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