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The Beauty of Clustered DNA Lesion

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 13405

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Prof. Dr. Boleslaw Karwowski

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DNA Damage Laboratory of Food Science Department, Faculty of Pharmacy, Medical University of Lodz, Lodz, Poland
Interests: DNA damage and repair; oligonucleotides and analogues synthesis; nucleic acids biochemistry; NMR; theoretical chemistry; DNA charge transfer; antioxidants; nutrition
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Dear Colleagues,

Local multi-damage sites (LMDS) such as DNA double-strand breaks (DSBs), inter-, or intra-strand cross-links are repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ) systems. The mentioned repair mechanisms have been well recognized in the case of isolated lesions, while the repair process of clustered DNA lesions still requires further study. The isolated DSB, which has been known for 70 years, is well recognized, but multi-DSB sites or clustered lesions (CL) composed of different types of damage, are not, especially in the context of the cellular response. Clustered DNA lesion has been defined as two or more cases of DNA damage per one or two helix turn. The significance of CL was discerned by Ward and Goodhead, whereas Price identified their presence and significance in E. coli. Additionally, it has been confirmed that clustered lesions are induced in mammalian cells. It is estimated that 80% of all LMDS sites contain damage that is not caused by DSBs. It should be pointed out that CLs are composed of DNA damage subunits, which are recognized and removed mainly by BER or the more complicated NER system. Moreover, using the Monte Carlo approach, it has been predicted that high-LET radiation is able to generate up to 25 clustered lesions at a distance of 200 nucleobase pairs. Based on the Bragg peak, it is not surprising that low-LET possesses the ability to induce LMDS too.

It is a great pleasure to invite fellow members of the scientific community to submit a manuscript (regular articles, communications, reviews) to this Special Issue.

Prof. Dr. Boleslaw Karwowski
Guest Editor

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Keywords

clustered DNA damage
DNA repair
DNA double-strand break
ionization radiation
radio- and chemotherapy
high and low linear energy transfer

Published Papers (5 papers)

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Research

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16 pages, 5756 KiB

Open AccessArticle

The Effect of Dia2 Protein Deficiency on the Cell Cycle, Cell Size, and Recruitment of Ctf4 Protein in Saccharomyces cerevisiae

by Aneliya Ivanova, Aleksandar Atemin, Sonya Uzunova, Georgi Danovski, Radoslav Aleksandrov, Stoyno Stoynov and Marina Nedelcheva-Veleva

Molecules 2022, 27(1), 97; https://doi.org/10.3390/molecules27010097 - 24 Dec 2021

Cited by 1 | Viewed by 2500

Abstract

Cells have evolved elaborate mechanisms to regulate DNA replication machinery and cell cycles in response to DNA damage and replication stress in order to prevent genomic instability and cancer. The E3 ubiquitin ligase SCF^Dia2 in S. cerevisiae is involved in the DNA replication and DNA damage stress response, but its effect on cell growth is still unclear. Here, we demonstrate that the absence of Dia2 prolongs the cell cycle by extending both S- and G2/M-phases while, at the same time, activating the S-phase checkpoint. In these conditions, Ctf4—an essential DNA replication protein and substrate of Dia2—prolongs its binding to the chromatin during the extended S- and G2/M-phases. Notably, the prolonged cell cycle when Dia2 is absent is accompanied by a marked increase in cell size. We found that while both DNA replication inhibition and an absence of Dia2 exerts effects on cell cycle duration and cell size, Dia2 deficiency leads to a much more profound increase in cell size and a substantially lesser effect on cell cycle duration compared to DNA replication inhibition. Our results suggest that the increased cell size in dia2∆ involves a complex mechanism in which the prolonged cell cycle is one of the driving forces. Full article

(This article belongs to the Special Issue The Beauty of Clustered DNA Lesion)

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14 pages, 2139 KiB

Open AccessArticle

In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach

by Athanasia Pavlopoulou, Seyedehsadaf Asfa, Evangelos Gioukakis, Ifigeneia V. Mavragani, Zacharenia Nikitaki, Işıl Takan, Jean-Pierre Pouget, Lynn Harrison and Alexandros G. Georgakilas

Molecules 2021, 26(24), 7602; https://doi.org/10.3390/molecules26247602 - 15 Dec 2021

Cited by 2 | Viewed by 2526

Abstract

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as “clustered/complex DNA damage” and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients. Full article

(This article belongs to the Special Issue The Beauty of Clustered DNA Lesion)

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12 pages, 1591 KiB

Open AccessArticle

The Influence of 5′,8-Cyclo-2′-deoxypurines on the Mitochondrial Repair of Clustered DNA Damage in Xrs5 Cells: The Preliminary Study

by Karolina Boguszewska, Julia Kaźmierczak-Barańska and Bolesław T. Karwowski

Molecules 2021, 26(22), 7042; https://doi.org/10.3390/molecules26227042 - 22 Nov 2021

Cited by 3 | Viewed by 1416

Abstract

The 5′,8-cyclo-2′-deoxypurines (cdPus) affect the DNA structure. When these bulky structures are a part of clustered DNA lesions (CDL), they affect the repair of the other lesions within the cluster. Mitochondria are crucial for cell survival and have their own genome, hence, are highly interesting in the context of CDL repair. However, no studies are exploring this topic. Here, the initial stages of mitochondrial base excision repair (mtBER) were considered—the strand incision and elongation. The repair of a single lesion (apurinic site (AP site)) accompanying the cdPu within the double-stranded CDL has been investigated for the first time. The type of cdPu, its diastereomeric form, and the interlesion distance were taken into consideration. For these studies, the established experimental model of short oligonucleotides (containing AP sites located ≤7 base pairs to the cdPu in both directions) and mitochondrial extracts of the xrs5 cells were used. The obtained results have shown that the presence of cdPus influenced the processing of an AP site within the CDL. Levels of strand incision and elongation were higher for oligos containing RcdA and ScdG than for those with ScdA and RcdG. Investigated stages of mtBER were more efficient for DNA containing AP sites located on 5′-end side of cdPu than on its 3′-end side. In conclusion, the presence of cdPus in mtDNA structure may affect mtBER (processing the second mutagenic lesion within the CDL). As impaired repair processes may lead to serious biological consequences, further studies concerning the mitochondrial repair of CDL are highly demanded. Full article

(This article belongs to the Special Issue The Beauty of Clustered DNA Lesion)

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13 pages, 8227 KiB

Open AccessArticle

Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1

by Tao Jiang, Antonio Monari, Elise Dumont and Emmanuelle Bignon

Molecules 2021, 26(21), 6465; https://doi.org/10.3390/molecules26216465 - 26 Oct 2021

Cited by 5 | Viewed by 1657

Abstract

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, which ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features, and repair have been matters of extensive research; more recently, this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use

μ

s-range molecular dynamics simulations and machine-learning-based postanalysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple-lesion site with a mismatch in 5

^{'}

or 3

^{'}

. We delineate the stiffening of the DNA–protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5

^{'}

mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion. Full article

(This article belongs to the Special Issue The Beauty of Clustered DNA Lesion)

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Review

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18 pages, 1024 KiB

Open AccessReview

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

by Veronika Mladenova, Emil Mladenov, Martin Stuschke and George Iliakis

Molecules 2022, 27(5), 1540; https://doi.org/10.3390/molecules27051540 - 24 Feb 2022

Cited by 22 | Viewed by 4433

Abstract

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel. Full article

(This article belongs to the Special Issue The Beauty of Clustered DNA Lesion)

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