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DNA Damage and DNA Repair in Cancer

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Nucleic Acids".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 12184

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Prof. Dr. Alexandros Georgakilas

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Guest Editor

DNA Damage Laboratory, Department of Physics, School of Applied Mathematical and Physical Sciences, Zografou Campus, National Technical University of Athens (NTUA), 15780 Athens, Greece
Interests: DNA damage; DNA repair; cancer; radiation therapy; bioinformatics

Prof. Dr. Lorenzo Manti

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Guest Editor

Radiation Biophysics Laboratory, Department of Physics, University of Naples Federico II, Complesso Universitario di Monte Sant’Angelo, Via Cinthia, 80126 Naples, Italy
Interests: radiation-induced chromosome aberrations; DNA repair; hadrontherapy; radiosensitization and radioprotection
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Special Issue Information

Dear Colleagues,

This Special Issue focuses on the most recent insights on the role(s) that DNA damage and repair have on cancer development and therapy. The maintenance of DNA integrity and the fidelity of the repair of exogenous as well as endogenous DNA damage as the main barrier against cellular transformation is a tenet in carcinogenesis. Cancerous cells are commonly viewed as lacking repair proficiency or harbouring defective biomolecular pathways compared to non-cancer cells. At the same time, many forms of anticancer strategies rely on further impairing cancer cell repair ability. However, how the latter is achieved varies according to whether the anticancer agent is a chemical or ionizing radiation, for example. Understanding how cancer may continue to progress in the face of incorrect lesion restitution and immune system evasion is arguably a crucial target of interdisciplinary research. Moreover, the complex interactions that take place within the microenvironment in which the initiating steps of transformation occur and possible systemic effects play a pivotal role in establishing features, such as resilience to chemo/radiotherapy, as well as proneness to acquire an aggressive phenotype.

Therefore, in this Special Issue, we welcome original basic research carried out by pre-clinical in vitro and/or in vivo approaches, as well as up-to-date reviews on these topics, with special emphasis on the novel frontiers in the fields of radiotherapy, immunotherapy and anticancer molecular targets.

Prof. Dr. Alexandros Georgakilas
Prof. Dr. Lorenzo Manti
Guest Editors

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Keywords

DNA damage
DNA repair
cancer
therapy
radiation biology
systems biology

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Published Papers (6 papers)

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Research

19 pages, 4847 KiB

Open AccessArticle

SNP-Associated Substitutions of Amino Acid Residues in the dNTP Selection Subdomain Decrease Polβ Polymerase Activity

by Olga A. Kladova, Timofey E. Tyugashev, Aleksandr A. Miroshnikov, Daria S. Novopashina, Nikita A. Kuznetsov and Aleksandra A. Kuznetsova

Biomolecules 2024, 14(5), 547; https://doi.org/10.3390/biom14050547 - 2 May 2024

Viewed by 1490

Abstract

In the cell, DNA polymerase β (Polβ) is involved in many processes aimed at maintaining genome stability and is considered the main repair DNA polymerase participating in base excision repair (BER). Polβ can fill DNA gaps formed by other DNA repair enzymes. Single-nucleotide polymorphisms (SNPs) in the POLB gene can affect the enzymatic properties of the resulting protein, owing to possible amino acid substitutions. For many SNP-associated Polβ variants, an association with cancer, owing to changes in polymerase activity and fidelity, has been shown. In this work, kinetic analyses and molecular dynamics simulations were used to examine the activity of naturally occurring polymorphic variants G274R, G290C, and R333W. Previously, the amino acid substitutions at these positions have been found in various types of tumors, implying a specific role of Gly-274, Gly-290, and Arg-333 in Polβ functioning. All three polymorphic variants had reduced polymerase activity. Two substitutions—G274R and R333W—led to the almost complete disappearance of gap-filling and primer elongation activities, a decrease in the deoxynucleotide triphosphate–binding ability, and a lower polymerization constant, due to alterations of local contacts near the replaced amino acid residues. Thus, variants G274R, G290C, and R333W may be implicated in an elevated level of unrepaired DNA damage. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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21 pages, 6817 KiB

Open AccessArticle

Differential Gene Expression in Human Fibroblasts Simultaneously Exposed to Ionizing Radiation and Simulated Microgravity

by Polina Malatesta, Konstantinos Kyriakidis, Megumi Hada, Hiroko Ikeda, Akihisa Takahashi, Premkumar B. Saganti, Alexandros G. Georgakilas and Ioannis Michalopoulos

Biomolecules 2024, 14(1), 88; https://doi.org/10.3390/biom14010088 - 10 Jan 2024

Viewed by 2726

Abstract

During future space missions, astronauts will be exposed to cosmic radiation and microgravity (μG), which are known to be health risk factors. To examine the differentially expressed genes (DEG) and their prevalent biological processes and pathways as a response to these two risk factors simultaneously, 1BR-hTERT human fibroblast cells were cultured under 1 gravity (1G) or simulated μG for 48 h in total and collected at 0 (sham irradiated), 3 or 24 h after 1 Gy of X-ray or Carbon-ion (C-ion) irradiation. A three-dimensional clinostat was used for the simulation of μG and the simultaneous radiation exposure of the samples. The RNA-seq method was used to produce lists of differentially expressed genes between different environmental conditions. Over-representation analyses were performed and the enriched biological pathways and targeting transcription factors were identified. Comparing sham-irradiated cells under simulated μG and 1G conditions, terms related to response to oxygen levels and muscle contraction were identified. After irradiation with X-rays or C-ions under 1G, identified DEGs were found to be involved in DNA damage repair, signal transduction by p53 class mediator, cell cycle arrest and apoptosis pathways. The same enriched pathways emerged when cells were irradiated under simulated μG condition. Nevertheless, the combined effect attenuated the transcriptional response to irradiation which may pose a subtle risk in space flights. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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13 pages, 1830 KiB

Open AccessArticle

Identifying Suitable Reference Gene Candidates for Quantification of DNA Damage-Induced Cellular Responses in Human U2OS Cell Culture System

by Nikolett Barta, Nóra Ördög, Vasiliki Pantazi, Ivett Berzsenyi, Barbara N. Borsos, Hajnalka Majoros, Zoltán G. Páhi, Zsuzsanna Ujfaludi and Tibor Pankotai

Biomolecules 2023, 13(10), 1523; https://doi.org/10.3390/biom13101523 - 13 Oct 2023

Viewed by 1757

Abstract

DNA repair pathways trigger robust downstream responses, making it challenging to select suitable reference genes for comparative studies. In this study, our goal was to identify the most suitable housekeeping genes to perform comparable molecular analyses for DNA damage-related studies. Choosing the most applicable reference genes is important in any kind of target gene expression-related quantitative study, since using the housekeeping genes improperly may result in false data interpretation and inaccurate conclusions. We evaluated the expressional changes of eight well-known housekeeping genes (i.e., 18S rRNA, B2M, eEF1α1, GAPDH, GUSB, HPRT1, PPIA, and TBP) following treatment with the DNA-damaging agents that are most frequently used: ultraviolet B (UVB) non-ionizing irradiation, neocarzinostatin (NCS), and actinomycin D (ActD). To reveal the significant changes in the expression of each gene and to determine which appear to be the most acceptable ones for normalization of real-time quantitative polymerase chain reaction (RT-qPCR) data, comparative and statistical algorithms (such as absolute quantification, Wilcoxon Rank Sum Test, and independent samples T-test) were conducted. Our findings clearly demonstrate that the genes commonly employed as reference candidates exhibit substantial expression variability, and therefore, careful consideration must be taken when designing the experimental setup for an accurate and reproducible normalization of RT-qPCR data. We used the U2OS cell line since it is generally accepted and used in the field of DNA repair to study DNA damage-induced cellular responses. Based on our current data in U2OS cells, we suggest using 18S rRNA, eEF1α1, GAPDH, GUSB, and HPRT1 genes for UVB-induced DNA damage-related studies. B2M, HPRT1, and TBP genes are recommended for NCS treatment, while 18S rRNA, B2M, and PPIA genes can be used as suitable internal controls in RT-qPCR experiments for ActD treatment. In summary, this is the first systematic study using a U2OS cell culture system that offers convincing evidence for housekeeping gene selection following treatment with various DNA-damaging agents. Here, we unravel an indispensable issue for performing and assessing trustworthy DNA damage-related differential gene expressional analyses, and we create a “zero set” of potential reference gene candidates. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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17 pages, 5733 KiB

Open AccessArticle

Nano-Architecture of Persistent Focal DNA Damage Regions in the Minipig Epidermis Weeks after Acute γ-Irradiation

by Harry Scherthan, Beatrice Geiger, David Ridinger, Jessica Müller, Diane Riccobono, Felix Bestvater, Matthias Port and Michael Hausmann

Biomolecules 2023, 13(10), 1518; https://doi.org/10.3390/biom13101518 - 13 Oct 2023

Viewed by 1762

Abstract

Exposure to high acute doses of ionizing radiation (IR) can induce cutaneous radiation syndrome. Weeks after such radiation insults, keratinocyte nuclei of the epidermis exhibit persisting genomic lesions that present as focal accumulations of DNA double-strand break (DSB) damage marker proteins. Knowledge about the nanostructure of these genomic lesions is scarce. Here, we compared the chromatin nano-architecture with respect to DNA damage response (DDR) factors in persistent genomic DNA damage regions and healthy chromatin in epidermis sections of two minipigs 28 days after lumbar irradiation with ~50 Gy γ-rays, using single-molecule localization microscopy (SMLM) combined with geometric and topological mathematical analyses. SMLM analysis of fluorochrome-stained paraffin sections revealed, within keratinocyte nuclei with perisitent DNA damage, the nano-arrangements of pATM, 53BP1 and Mre11 DDR proteins in γ-H2AX-positive focal chromatin areas (termed macro-foci). It was found that persistent macro-foci contained on average ~70% of 53BP1, ~23% of MRE11 and ~25% of pATM single molecule signals of a nucleus. MRE11 and pATM fluorescent tags were organized in focal nanoclusters peaking at about 40 nm diameter, while 53BP1 tags formed nanoclusters that made up super-foci of about 300 nm in size. Relative to undamaged nuclear chromatin, the enrichment of DDR protein signal tags in γ-H2AX macro-foci was on average 8.7-fold (±3) for 53BP1, 3.4-fold (±1.3) for MRE11 and 3.6-fold (±1.8) for pATM. The persistent macro-foci of minipig epidermis displayed a ~2-fold enrichment of DDR proteins, relative to DSB foci of lymphoblastoid control cells 30 min after 0.5 Gy X-ray exposure. A lasting accumulation of damage signaling and sensing molecules such as pATM and 53BP1, as well as the DSB end-processing protein MRE11 in the persistent macro-foci suggests the presence of diverse DNA damages which pose an insurmountable problem for DSB repair. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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18 pages, 6087 KiB

Open AccessArticle

Transition Mutations in the hTERT Promoter Are Unrelated to Potential i-motif Formation in the C-Rich Strand

by James W. Conrad, Mark L. Sowers, Dianne Y. Yap, Ellie Cherryhomes, B. Montgomery Pettitt, Kamil Khanipov and Lawrence C. Sowers

Biomolecules 2023, 13(9), 1308; https://doi.org/10.3390/biom13091308 - 25 Aug 2023

Viewed by 1652

Abstract

Increased expression of the human telomere reverse transcriptase (hTERT) in tumors promotes tumor cell survival and diminishes the survival of patients. Cytosine-to-thymine (C-to-T) transition mutations (C250T or C228T) in the hTERT promoter create binding sites for transcription factors, which enhance transcription. The G-rich strand of the hTERT promoter can form G-quadruplex structures, whereas the C-rich strand can form an i-motif in which multiple cytosine residues are protonated. We considered the possibility that i-motif formation might promote cytosine deamination to uracil and C-to-T mutations. We computationally probed the accessibility of cytosine residues in an i-motif to attack by water. We experimentally examined regions of the C-rich strand to form i-motifs using pH-dependent UV and CD spectra. We then incubated the C-rich strand with and without the G-rich complementary strand DNA under various conditions, followed by deep sequencing. Surprisingly, deamination rates did not vary substantially across the 46 cytosines examined, and the two mutation hotspots were not deamination hotspots. The appearance of mutational hotspots in tumors is more likely the result of the selection of sequences with increased promoter binding affinity and hTERT expression. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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23 pages, 2458 KiB

Open AccessEditor’s ChoiceArticle

How Clustered DNA Damage Can Change the Electronic Properties of ds-DNA—Differences between GAG, GA^OXOG, and ^OXOGA^OXOG

by Boleslaw Karwowski

Biomolecules 2023, 13(3), 517; https://doi.org/10.3390/biom13030517 - 11 Mar 2023

Cited by 5 | Viewed by 1605

Abstract

Every 24 h, roughly 3 × 10¹⁷ incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in the clustered DNA damage (CDL) level during anticancer treatment have been observed compared to those found in untreated normal tissues. 7,8-dihydro-8-oxo-2′-deoxyguanosine (^OXOG) has been recognized as the most common lesion. In these studies, the influence of ^OXOG, as an isolated (oligo-^OG) or clustered DNA lesion (oligo-^OG^OG), on charge transfer has been analyzed in comparison to native oligo-G. DNA lesion repair depends on the damage recognition step, probably via charge transfer. Here the electronic properties of short ds-oligonucleotides were calculated and analyzed at the M062x/6-31++G** level of theory in a non-equilibrated and equilibrated solvent state. The rate constant of hole and electron transfer according to Marcus’ theory was also discussed. These studies elucidated that ^OXOG constitutes the sink for migrated radical cations. However, in the case of oligo-^OG^OG containing a 5′-^OXOGA^XOXG-3′ sequence, the 3′-End ^OXOG becomes predisposed to electron-hole accumulation contrary to the undamaged GAG fragment. Moreover, it was found that the 5′-End ^OXOG present in an ^OXOGA^OXOG fragment adopts a higher adiabatic ionization potential than the 2′-deoxyguanosine of an undamaged analog if both ds-oligos are present in a cationic form. Because increases in CDL formation have been observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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