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DNA Damage Response Mechanisms in Model Systems
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DNA Damage Response Mechanisms in Model Systems

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 January 2022) | Viewed by 37376

Special Issue Editors

Dr. Jan LaRocque

E-Mail Website
Guest Editor
Department of Human Science, School of Nursing and Health Studies, Georgetown University, 265 St. Mary's Hall, 3700 Reservoir Road NW, Washington, DC 20057-1107, USA
Interests: DNA double-strand break repair; Drosophila; homologous recombination; DNA repair; genomic instability
Dr. Mitch McVey

E-Mail Website
Guest Editor
Department of Biology, Tufts University, 200 Boston Ave., Suite 4741, Medford, MA 02155, USA
Interests: mutagenesis; damage tolerance; alternative end joining; DNA polymerases; aging

Special Issue Information

Dear Colleagues,

Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome integrity. To deal with this, organisms have evolved a myriad of responses, including transcriptional programs, cell cycle regulation, lesion bypass, and direct repair. While much of the research describing these responses has utilized mammalian cell culture systems, studies performed in model organisms have also provided critical insight into the organismal regulation of damage responses. This Special Issue will highlight discoveries made in the areas of DNA repair and damage responses, with an emphasis on findings from model systems. High-quality investigations and reviews that discuss recent advances and future challenges in the fields of DNA repair and damage response systems are welcomed.

Dr. Jan LaRocque
Dr. Mitch McVey
Guest Editors

Manuscript Submission Information

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Keywords

  • DNA damage
  • DNA repair
  • model organisms
  • DNA damage response
  • cell cycle checkpoint
  • double-strand break repair
  • nucleotide excision repair
  • mismatch repair
  • mutagenesis/damage tolerance

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 173 KiB  
Editorial
DNA Damage Response Mechanisms in Model Systems
by Jeannine R. LaRocque and Mitch McVey
Genes 2023, 14(7), 1385; https://doi.org/10.3390/genes14071385 - 30 Jun 2023
Viewed by 1601
Abstract
Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...] Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)

Research

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14 pages, 2069 KiB  
Article
Division of Labor by the HELQ, BLM, and FANCM Helicases during Homologous Recombination Repair in Drosophila melanogaster
by Adam Thomas, Julie Cox, Kelly B. Wolfe, Carrie Hui Mingalone, Haleigh R. Yaspan and Mitch McVey
Genes 2022, 13(3), 474; https://doi.org/10.3390/genes13030474 - 8 Mar 2022
Cited by 7 | Viewed by 3058
Abstract
Repair of DNA double-strand breaks by homologous recombination (HR) requires a carefully orchestrated sequence of events involving many proteins. One type of HR, synthesis-dependent strand annealing (SDSA), proceeds via the formation of a displacement loop (D-loop) when RAD51-coated single-stranded DNA invades a homologous [...] Read more.
Repair of DNA double-strand breaks by homologous recombination (HR) requires a carefully orchestrated sequence of events involving many proteins. One type of HR, synthesis-dependent strand annealing (SDSA), proceeds via the formation of a displacement loop (D-loop) when RAD51-coated single-stranded DNA invades a homologous template. The 3′ end of the single-stranded DNA is extended by DNA synthesis. In SDSA, the D-loop is then disassembled prior to strand annealing. While many helicases can unwind D-loops in vitro, how their action is choreographed in vivo remains to be determined. To clarify the roles of various DNA helicases during SDSA, we used a double-strand gap repair assay to study the outcomes of homologous recombination repair in Drosophila melanogaster lacking the BLM, HELQ, and FANCM helicases. We found that the absence of any of these three helicases impairs gap repair. In addition, flies lacking both BLM and HELQ or HELQ and FANCM had more severe SDSA defects than the corresponding single mutants. In the absence of BLM, a large percentage of repair events were accompanied by flanking deletions. Strikingly, these deletions were mostly abolished in the blm helq and blm fancm double mutants. Our results suggest that the BLM, HELQ, and FANCM helicases play distinct roles during SDSA, with HELQ and FANCM acting early to promote the formation of recombination intermediates that are then processed by BLM to prevent repair by deletion-prone mechanisms. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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10 pages, 1751 KiB  
Article
The Drosophila Mutagen-Sensitivity Gene mus109 Encodes DmDNA2
by Chandani Mitchell, Vada Becker, Jordan DeLoach, Erica Nestore, Elyse Bolterstein and Kathryn P. Kohl
Genes 2022, 13(2), 312; https://doi.org/10.3390/genes13020312 - 7 Feb 2022
Cited by 3 | Viewed by 2815
Abstract
The identification of mutants through forward genetic screens is the backbone of Drosophila genetics research, yet many mutants identified through these screens have yet to be mapped to the Drosophila genome. This is especially true of mutants that have been identified as mutagen-sensitive [...] Read more.
The identification of mutants through forward genetic screens is the backbone of Drosophila genetics research, yet many mutants identified through these screens have yet to be mapped to the Drosophila genome. This is especially true of mutants that have been identified as mutagen-sensitive (mus), but have not yet been mapped to their associated molecular locus. Our study addressed the need for additional mus gene identification by determining the locus and exploring the function of the X-linked mutagen-sensitive gene mus109 using three available mutant alleles: mus109D1, mus109D2, and mus109lS. After first confirming that all three mus109 alleles were sensitive to methyl methanesulfonate (MMS) using complementation analysis, we used deletion mapping to narrow the candidate genes for mus109. Through DNA sequencing, we were able to determine that mus109 is the uncharacterized gene CG2990, which encodes the Drosophila ortholog of the highly conserved DNA2 protein that is important for DNA replication and repair. We further used the sequence and structure of DNA2 to predict the impact of the mus109 allele mutations on the final gene product. Together, these results provide a tool for researchers to further investigate the role of DNA2 in DNA repair processes in Drosophila. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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11 pages, 1926 KiB  
Article
A Simulated Shift Work Schedule Does Not Increase DNA Double-Strand Break Repair by NHEJ in the Drosophila Rr3 System
by Lydia Bergerson, Caleb Fitzmaurice, Tyler Knudtson, Halle McCormick and Alder M. Yu
Genes 2022, 13(1), 150; https://doi.org/10.3390/genes13010150 - 15 Jan 2022
Cited by 2 | Viewed by 2466
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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14 pages, 1084 KiB  
Article
The Role of Drosophila CtIP in Homology-Directed Repair of DNA Double-Strand Breaks
by Ian Yannuzzi, Margaret A. Butler, Joel Fernandez and Jeannine R. LaRocque
Genes 2021, 12(9), 1430; https://doi.org/10.3390/genes12091430 - 16 Sep 2021
Cited by 4 | Viewed by 4643
Abstract
DNA double-strand breaks (DSBs) are a particularly genotoxic type of DNA damage that can result in chromosomal aberrations. Thus, proper repair of DSBs is essential to maintaining genome integrity. DSBs can be repaired by non-homologous end joining (NHEJ), where ends are processed before [...] Read more.
DNA double-strand breaks (DSBs) are a particularly genotoxic type of DNA damage that can result in chromosomal aberrations. Thus, proper repair of DSBs is essential to maintaining genome integrity. DSBs can be repaired by non-homologous end joining (NHEJ), where ends are processed before joining through ligation. Alternatively, DSBs can be repaired through homology-directed repair, either by homologous recombination (HR) or single-strand annealing (SSA). Both types of homology-directed repair are initiated by DNA end resection. In cultured human cells, the protein CtIP has been shown to play a role in DNA end resection through its interactions with CDK, BRCA1, DNA2, and the MRN complex. To elucidate the role of CtIP in a multicellular context, CRISPR/Cas9 genome editing was used to create a DmCtIPΔ allele in Drosophila melanogaster. Using the DSB repair reporter assay direct repeat of white (DR-white), a two-fold decrease in HR in DmCtIPΔ/Δ mutants was observed when compared to heterozygous controls. However, analysis of HR gene conversion tracts (GCTs) suggests DmCtIP plays a minimal role in determining GCT length. To assess the function of DmCtIP on both short (~550 bp) and long (~3.6 kb) end resection, modified homology-directed SSA repair assays were implemented, resulting in a two-fold decrease in SSA repair in both short and extensive end resection requirements in the DmCtIPΔ/Δ mutants compared to heterozygote controls. Through these analyses, we affirmed the importance of end resection on DSB repair pathway choice in multicellular systems, described the function of DmCtIP in short and extensive DNA end resection, and determined the impact of end resection on GCT length during HR. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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Review

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23 pages, 2614 KiB  
Review
An Expanding Toolkit for Heterochromatin Repair Studies
by Chetan C. Rawal, Nadejda L. Butova, Anik Mitra and Irene Chiolo
Genes 2022, 13(3), 529; https://doi.org/10.3390/genes13030529 - 17 Mar 2022
Cited by 4 | Viewed by 3953
Abstract
Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to enable ‘safe’ homologous recombination (HR) repair while preventing aberrant recombination in this domain. Understanding heterochromatin repair responses is essential to understanding the critical [...] Read more.
Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to enable ‘safe’ homologous recombination (HR) repair while preventing aberrant recombination in this domain. Understanding heterochromatin repair responses is essential to understanding the critical mechanisms responsible for genome integrity and tumor suppression. Here, we review the tools, approaches, and methods currently available to investigate double-strand break (DSB) repair in pericentromeric regions, and also suggest how technologies recently developed for euchromatin repair studies can be adapted to characterize responses in heterochromatin. With this ever-growing toolkit, we are witnessing exciting progress in our understanding of how the ‘dark matter’ of the genome is repaired, greatly improving our understanding of genome stability mechanisms. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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16 pages, 1368 KiB  
Review
DNA Double-Strand Break Repairs and Their Application in Plant DNA Integration
by Hexi Shen and Zhao Li
Genes 2022, 13(2), 322; https://doi.org/10.3390/genes13020322 - 9 Feb 2022
Cited by 18 | Viewed by 8289
Abstract
Double-strand breaks (DSBs) are considered to be one of the most harmful and mutagenic forms of DNA damage. They are highly toxic if unrepaired, and can cause genome rearrangements and even cell death. Cells employ two major pathways to repair DSBs: homologous recombination [...] Read more.
Double-strand breaks (DSBs) are considered to be one of the most harmful and mutagenic forms of DNA damage. They are highly toxic if unrepaired, and can cause genome rearrangements and even cell death. Cells employ two major pathways to repair DSBs: homologous recombination (HR) and non-homologous end-joining (NHEJ). In plants, most applications of genome modification techniques depend on the development of DSB repair pathways, such as Agrobacterium-mediated transformation (AMT) and gene targeting (GT). In this paper, we review the achieved knowledge and recent advances on the DNA DSB response and its main repair pathways; discuss how these pathways affect Agrobacterium-mediated T-DNA integration and gene targeting in plants; and describe promising strategies for producing DSBs artificially, at definite sites in the genome. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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16 pages, 1143 KiB  
Review
DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond
by Delisa E. Clay and Donald T. Fox
Genes 2021, 12(12), 1882; https://doi.org/10.3390/genes12121882 - 25 Nov 2021
Cited by 36 | Viewed by 4304
Abstract
Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress [...] Read more.
Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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17 pages, 1275 KiB  
Review
The Sound of Silence: How Silenced Chromatin Orchestrates the Repair of Double-Strand Breaks
by Apfrida Kendek, Marieke R. Wensveen and Aniek Janssen
Genes 2021, 12(9), 1415; https://doi.org/10.3390/genes12091415 - 15 Sep 2021
Cited by 6 | Viewed by 4434
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue DNA Damage Response Mechanisms in Model Systems)
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