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Dynamics of DNA Double Strand Breaks
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Dynamics of DNA Double Strand Breaks

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 July 2022) | Viewed by 23134

Special Issue Editor

Dr. Josee Guirouilh-Barbat

E-Mail Website
Guest Editor
Institut Cochin, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
Interests: DNA repair; DNA double-strand break; non-homologous end joining; homologous recombination; alternative end joining; genome stability; chromosomal rearrangements

Special Issue Information

Dear Colleagues,

A DNA double-strand break (DSB) is one of the most toxic lesions for a cell. Repair systems exist that aim at maintaining genomic integrity, including non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ roughly and quickly ligates two DNA double-strand ends. HR is a more sophisticated pathway that searches a homologous partner in the genome and uses it as a template to restore the original sequence. NHEJ and HR guarantee the integrity of the genome, but are also generators of genomic instability: both can lead to rearrangements eventually associated to mutagenesis at the junction. Among other risks, finding the right partner is crucial. NHEJ between originally distant DNA ends leads to deletions, inversions, or translocations. HR between repeated sequences generates rearrangements. Avoiding these events is a keystone in the preservation of genomic integrity. In addition to HR and NHEJ, other DSB repair pathways exist that are necessarily mutagenic. They mostly rely on the use of microhomologies, which is quite a risky way to repair DSBs. Their outcomes are deletions and/or translocations, sometimes coupled to insertions. These pathways must be “last-resort” options, used when DSBs cannot be repaired by the more conservative HR and NHEJ.

Thus, the choices of the right pathway and the right partner are pivotal and are regulated by multiple safeguards, including the cell cycle phase, the chromatin context, and the nuclear compartment. In this Special Issue we propose to discuss how DSBs are transmitted along the cell cycle to be repaired in the appropriate phase. We will also examine where and how DSBs move in the nuclear compartment and how the chromatin context influences the outcome of the repair.

Dr. Josee Guirouilh-Barbat
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA double-strand breaks
  • DSB dynamics
  • Nuclear organization
  • DNA damage response
  • Chromatin
  • DSB repair pathway choice
  • Homologous recombination
  • Non-homologous end joining
  • Cell cycle phase

Published Papers (6 papers)

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Review

21 pages, 2452 KiB  
Review
53BP1: Keeping It under Control, Even at a Distance from DNA Damage
by Emilie Rass, Simon Willaume and Pascale Bertrand
Genes 2022, 13(12), 2390; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13122390 - 16 Dec 2022
Cited by 9 | Viewed by 5668
Abstract
Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J recombination. The repair of these DSBs is crucial to prevent genomic instability and to maintain cellular homeostasis. Two main pathways [...] Read more.
Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J recombination. The repair of these DSBs is crucial to prevent genomic instability and to maintain cellular homeostasis. Two main pathways participate in repairing DSBs, namely, non-homologous end joining (NHEJ) and homologous recombination (HR). The P53-binding protein 1 (53BP1) plays a pivotal role in the choice of DSB repair mechanism, promotes checkpoint activation and preserves genome stability upon DSBs. By preventing DSB end resection, 53BP1 promotes NHEJ over HR. Nonetheless, the balance between DSB repair pathways remains crucial, as unscheduled NHEJ or HR events at different phases of the cell cycle may lead to genomic instability. Therefore, the recruitment of 53BP1 to chromatin is tightly regulated and has been widely studied. However, less is known about the mechanism regulating 53BP1 recruitment at a distance from the DNA damage. The present review focuses on the mechanism of 53BP1 recruitment to damage and on recent studies describing novel mechanisms keeping 53BP1 at a distance from DSBs. Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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21 pages, 2352 KiB  
Review
Repair Foci as Liquid Phase Separation: Evidence and Limitations
by Judith Miné-Hattab, Siyu Liu and Angela Taddei
Genes 2022, 13(10), 1846; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101846 - 13 Oct 2022
Cited by 7 | Viewed by 2743
Abstract
In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or “foci”. The formation of these foci and their disassembly within the proper time window are essential for genome integrity. However, how these membrane-less sub-compartments are [...] Read more.
In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or “foci”. The formation of these foci and their disassembly within the proper time window are essential for genome integrity. However, how these membrane-less sub-compartments are formed, maintained and disassembled remains unclear. Recently, several studies across different model organisms proposed that DNA repair foci form via liquid phase separation. In this review, we discuss the current research investigating the physical nature of repair foci. First, we present the different models of condensates proposed in the literature, highlighting the criteria to differentiate them. Second, we discuss evidence of liquid phase separation at DNA repair sites and the limitations of this model to fully describe structures formed in response to DNA damage. Finally, we discuss the origin and possible function of liquid phase separation for DNA repair processes. Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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22 pages, 1711 KiB  
Review
The Dynamic Behavior of Chromatin in Response to DNA Double-Strand Breaks
by Fabiola García Fernández and Emmanuelle Fabre
Genes 2022, 13(2), 215; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020215 - 25 Jan 2022
Cited by 10 | Viewed by 3334
Abstract
The primary functions of the eukaryotic nucleus as a site for the storage, retrieval, and replication of information require a highly dynamic chromatin organization, which can be affected by the presence of DNA damage. In response to double-strand breaks (DSBs), the mobility of [...] Read more.
The primary functions of the eukaryotic nucleus as a site for the storage, retrieval, and replication of information require a highly dynamic chromatin organization, which can be affected by the presence of DNA damage. In response to double-strand breaks (DSBs), the mobility of chromatin at the break site is severely affected and, to a lesser extent, that of other chromosomes. The how and why of such movement has been widely studied over the last two decades, leading to different mechanistic models and proposed potential roles underlying both local and global mobility. Here, we review the state of the knowledge on current issues affecting chromatin mobility upon DSBs, and highlight its role as a crucial step in the DNA damage response (DDR). Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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20 pages, 1727 KiB  
Review
DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex
by Jamie Phipps and Karine Dubrana
Genes 2022, 13(2), 198; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020198 - 22 Jan 2022
Cited by 10 | Viewed by 4888
Abstract
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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14 pages, 1437 KiB  
Review
SUMO-Based Regulation of Nuclear Positioning to Spatially Regulate Homologous Recombination Activities at Replication Stress Sites
by Kamila Schirmeisen, Sarah A. E. Lambert and Karol Kramarz
Genes 2021, 12(12), 2010; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12122010 - 17 Dec 2021
Cited by 5 | Viewed by 2805
Abstract
DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one. Recent studies uncovered that the replication fork, when its progression is impaired, exhibits increased mobility when changing nuclear positioning and anchors to nuclear pore [...] Read more.
DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one. Recent studies uncovered that the replication fork, when its progression is impaired, exhibits increased mobility when changing nuclear positioning and anchors to nuclear pore complexes, where specific types of homologous recombination pathways take place. In yeast models, increasing evidence points out that nuclear positioning is regulated by small ubiquitin-like modifier (SUMO) metabolism, which is pivotal to maintaining genome integrity at sites of replication stress. Here, we review how SUMO-based pathways are instrumental to spatially segregate the subsequent steps of homologous recombination during replication fork restart. In particular, we discussed how routing towards nuclear pore complex anchorage allows distinct homologous recombination pathways to take place at halted replication forks. Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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13 pages, 558 KiB  
Review
Alternative Lengthening of Telomeres: Lessons to Be Learned from Telomeric DNA Double-Strand Break Repair
by Thomas Kent and David Clynes
Genes 2021, 12(11), 1734; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111734 - 29 Oct 2021
Cited by 6 | Viewed by 2806
Abstract
The study of the molecular pathways underlying cancer has given us important insights into how breaks in our DNA are repaired and the dire consequences that can occur when these processes are perturbed. Extensive research over the past 20 years has shown that [...] Read more.
The study of the molecular pathways underlying cancer has given us important insights into how breaks in our DNA are repaired and the dire consequences that can occur when these processes are perturbed. Extensive research over the past 20 years has shown that the key molecular event underpinning a subset of cancers involves the deregulated repair of DNA double-strand breaks (DSBs) at telomeres, which in turn leads to telomere lengthening and the potential for replicative immortality. Here we discuss, in-depth, recent major breakthroughs in our understanding of the mechanisms underpinning this pathway known as the alternative lengthening of telomeres (ALT). We explore how this gives us important insights into how DSB repair at telomeres is regulated, with relevance to the cell-cycle-dependent regulation of repair, repair of stalled replication forks and the spatial regulation of DSB repair. Full article
(This article belongs to the Special Issue Dynamics of DNA Double Strand Breaks)
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