Review ArticleCollaborations between chromatin and nuclear architecture to optimize DNA repair fidelity
Section snippets
Introduction to homologous recombination (HR): beneficial and deleterious outcomes
By querying the genome for optimal donor sequences for conservative repair, HR can accurately repair large numbers of DSBs within a single cell (Fig. 1). This process is arguably the highest fidelity mechanism by which DSBs are repaired. HR can also be attempted in situations where an ideal repair template is not available, resulting in repair outcomes that are often deleterious. Such HR outcomes can yield gross chromosomal rearrangements where large portions of a chromosome are translocated or
Chromatin facilitates rapid DSB repair through first choice HR pathways and is accompanied by a global increase in chromatin mobility
Cells orchestrate major changes in nuclear architecture to facilitate the rapid repair of a DSB. As first demonstrated in baker’s yeast, in the absence of DSBs, chromosomal loci within S-phase nuclei display small radii of confinement (∼3−10% of the nuclear volume) (Fig. 3; [[48], [49], [50], [51], [52], [53], [54], [55], [56], [57]] Upon induction of a DSB at a single locus, the affected locus and other undamaged genomic loci become more diffuse, sampling roughly 10 % and up to 50 % of the
Pre-invasion: sister chromatid cohesion makes the sister chromatid the most likely target
Equally important as the choice of specific HR repair pathway is the choice of donor sequence used as a template for repair. Current data indicate that this step is rate limiting for HR [61,62,92]. During this step, overall nuclear architecture and chromatin accessibility can have a significant impact on use of various potential donor templates [61,62,92]. As mentioned previously, the sister chromatid provides an ideal donor template; the corresponding locus on the undamaged sister chromatid
Conclusions and implications for our understanding recombinational repair decisions
This review is focused on understanding how cells choose specific HR subpathways. To answer this, one must understand how the recombination machinery and accompanying changes in nuclear architecture are coordinated. Work presented in this review indicates that the high-fidelity repair of a DSB by HR is an orchestrated set of events that involve changes in chromatin and nuclear architecture. By shuttling DSBs to different subnuclear compartments, the cell can prioritize fast and efficient
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
We thank Lucas Argueso, members of the Alani laboratory, and anonymous reviewers for helpful comments in the preparation of this manuscript. B.L.M. and E.A. are supported by the National Institute of General Medical Sciences of the National Institutes of Health: R35GM134872 to E.A. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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