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Molecular Mechanisms of Genotoxicity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 41692

Special Issue Editor

Special Issue Information

Dear colleagues,

Genetic information is carried by the DNA, which is constantly exposed and may be damaged by endogenous and exogenous agents. Thus, multiple cell mechanisms are guarantees that different types of DNA damage can be corrected. In addition, the ability to detect and properly repair these DNA damages is crucial for cells to survive and maintain a normal phenotype. Defective DNA repair results in a variety of outcomes, including genetic instability and cancer. Advances in the knowledge of molecular mechanisms involved will lead to a better understanding and increase chances of preventing such diseases or even lead to effective treatments.
The aim of this Special Issue is to provide an overview of the knowledge regarding the molecular mechanisms involved and development perspectives. We anticipate that the papers presented in this issue will be of valuable support for the scientific community, in diverse contexts such as cell biology, physiopathology, etc.

Dr. Gladys Mirey
Guest Editor

Manuscript Submission Information

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Keywords

  • molecular mechanisms
  • DNA damage
  • DNA repair
  • cell signaling
  • cellular outputs
  • genetic instability
  • cancer
  • assay development

Published Papers (6 papers)

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Research

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13 pages, 1582 KiB  
Article
New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?
by Gennaro Lettieri, Rosaria Notariale, Nadia Carusone, Antonella Giarra, Marco Trifuoggi, Caterina Manna and Marina Piscopo
Int. J. Mol. Sci. 2021, 22(11), 5893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115893 - 31 May 2021
Cited by 16 | Viewed by 2452
Abstract
Mercury (Hg) is a highly toxic and widespread pollutant. We previously reported that the exposure of Mytilus galloprovincialis for 24 h to doses of HgCl2 similar to those found in seawater (range 1–100 pM) produced alterations in the properties of protamine-like (PL) [...] Read more.
Mercury (Hg) is a highly toxic and widespread pollutant. We previously reported that the exposure of Mytilus galloprovincialis for 24 h to doses of HgCl2 similar to those found in seawater (range 1–100 pM) produced alterations in the properties of protamine-like (PL) proteins that rendered them unable to bind and protect DNA from oxidative damage. In the present work, to deepen our studies, we analyzed PL proteins by turbidimetry and fluorescence spectroscopy and performed salt-induced release analyses of these proteins from sperm nuclei after the exposure of mussels to HgCl2 at the same doses. Turbidity assays indicated that mercury, at these doses, induced PL protein aggregates, whereas fluorescence spectroscopy measurements showed mercury-induced conformational changes. Indeed, the mobility of the PLII band changed in sodium dodecyl sulphate-polyacrylamide gel electrophoresis, particularly after exposure to 10-pM HgCl2, confirming the mercury-induced structural rearrangement. Finally, exposure to HgCl2 at all doses produced alterations in PL-DNA binding, detectable by DNA absorption spectra after the PL protein addition and by a decreased release of PLII and PLIII from the sperm nuclei. In conclusion, in this paper, we reported Hg-induced PL protein alterations that could adversely affect mussel reproductive activity, providing an insight into the molecular mechanism of Hg-related infertility. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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17 pages, 1517 KiB  
Article
rad21 Is Involved in Corneal Stroma Development by Regulating Neural Crest Migration
by Bi Ning Zhang, Yu Liu, Qichen Yang, Pui Ying Leung, Chengdong Wang, Thomas Chi Bun Wong, Clement C. Tham, Sun On Chan, Chi Pui Pang, Li Jia Chen, Job Dekker, Hui Zhao and Wai Kit Chu
Int. J. Mol. Sci. 2020, 21(20), 7807; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207807 - 21 Oct 2020
Cited by 3 | Viewed by 2606
Abstract
Previously, we identified RAD21R450C from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were [...] Read more.
Previously, we identified RAD21R450C from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were performed using cells from family members affected by peripheral sclerocornea. Both gene expression and chromosome conformation of cell adhesion genes were affected in cells carrying the heterozygous rad21 variant. Since cell migration is essential in early embryonic development and sclerocornea is a congenital disease, we studied neural crest migration during cornea development in X. laevis embryos. In X. laevis embryos injected with rad21 mutant mRNA, neural crest migration was disrupted, and the number of neural crest-derived periocular mesenchymes decreased significantly in the corneal stroma region. Our data indicate that the RAD21R450C variant contributes to peripheral sclerocornea by modifying chromosome conformation and gene expression, therefore disturbing neural crest cell migration, which suggests RAD21 plays a key role in corneal stroma development. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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15 pages, 3391 KiB  
Article
Modulation of the Apurinic/Apyrimidinic Endonuclease Activity of Human APE1 and of Its Natural Polymorphic Variants by Base Excision Repair Proteins
by Olga A. Kladova, Irina V. Alekseeva, Murat Saparbaev, Olga S. Fedorova and Nikita A. Kuznetsov
Int. J. Mol. Sci. 2020, 21(19), 7147; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197147 - 28 Sep 2020
Cited by 12 | Viewed by 2134
Abstract
Human apurinic/apyrimidinic endonuclease 1 (APE1) is known to be a critical player of the base excision repair (BER) pathway. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that these proteins interact with [...] Read more.
Human apurinic/apyrimidinic endonuclease 1 (APE1) is known to be a critical player of the base excision repair (BER) pathway. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that these proteins interact with APE1 either at upstream or downstream steps of BER. Therefore, we may propose that even a minor disturbance of protein–protein interactions on the DNA template reduces coordination and repair efficiency. Here, the ability of various human DNA repair enzymes (such as DNA glycosylases OGG1, UNG2, and AAG; DNA polymerase Polβ; or accessory proteins XRCC1 and PCNA) to influence the activity of wild-type (WT) APE1 and its seven natural polymorphic variants (R221C, N222H, R237A, G241R, M270T, R274Q, and P311S) was tested. Förster resonance energy transfer–based kinetic analysis of abasic site cleavage in a model DNA substrate was conducted to detect the effects of interacting proteins on the activity of WT APE1 and its single-nucleotide polymorphism (SNP) variants. The results revealed that WT APE1 activity was stimulated by almost all tested DNA repair proteins. For the SNP variants, the matters were more complicated. Analysis of two SNP variants, R237A and G241R, suggested that a positive charge in this area of the APE1 surface impairs the protein–protein interactions. In contrast, variant R221C (where the affected residue is located near the DNA-binding site) showed permanently lower activation relative to WT APE1, whereas neighboring SNP N222H did not cause a noticeable difference as compared to WT APE1. Buried substitution P311S had an inconsistent effect, whereas each substitution at the DNA-binding site, M270T and R274Q, resulted in the lowest stimulation by BER proteins. Protein–protein molecular docking was performed between repair proteins to identify amino acid residues involved in their interactions. The data uncovered differences in the effects of BER proteins on APE1, indicating an important role of protein–protein interactions in the coordination of the repair pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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Review

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33 pages, 497 KiB  
Review
Manmade Electromagnetic Fields and Oxidative Stress—Biological Effects and Consequences for Health
by David Schuermann and Meike Mevissen
Int. J. Mol. Sci. 2021, 22(7), 3772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073772 - 06 Apr 2021
Cited by 74 | Viewed by 26034
Abstract
Concomitant with the ever-expanding use of electrical appliances and mobile communication systems, public and occupational exposure to electromagnetic fields (EMF) in the extremely-low-frequency and radiofrequency range has become a widely debated environmental risk factor for health. Radiofrequency (RF) EMF and extremely-low-frequency (ELF) MF [...] Read more.
Concomitant with the ever-expanding use of electrical appliances and mobile communication systems, public and occupational exposure to electromagnetic fields (EMF) in the extremely-low-frequency and radiofrequency range has become a widely debated environmental risk factor for health. Radiofrequency (RF) EMF and extremely-low-frequency (ELF) MF have been classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC). The production of reactive oxygen species (ROS), potentially leading to cellular or systemic oxidative stress, was frequently found to be influenced by EMF exposure in animals and cells. In this review, we summarize key experimental findings on oxidative stress related to EMF exposure from animal and cell studies of the last decade. The observations are discussed in the context of molecular mechanisms and functionalities relevant to health such as neurological function, genome stability, immune response, and reproduction. Most animal and many cell studies showed increased oxidative stress caused by RF-EMF and ELF-MF. In order to estimate the risk for human health by manmade exposure, experimental studies in humans and epidemiological studies need to be considered as well. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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26 pages, 1321 KiB  
Review
Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis
by Margarita A. Sazonova, Vasily V. Sinyov, Anastasia I. Ryzhkova, Marina D. Sazonova, Tatiana V. Kirichenko, Victoria A. Khotina, Zukhra B. Khasanova, Natalya A. Doroschuk, Vasily P. Karagodin, Alexander N. Orekhov and Igor A. Sobenin
Int. J. Mol. Sci. 2021, 22(2), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020699 - 12 Jan 2021
Cited by 12 | Viewed by 3379
Abstract
Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized [...] Read more.
Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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15 pages, 2025 KiB  
Review
Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation
by Kalaiyarasi Ragunathan, Nikki Lyn Esnardo Upfold and Valentyn Oksenych
Int. J. Mol. Sci. 2020, 21(22), 8635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228635 - 16 Nov 2020
Cited by 27 | Viewed by 4166
Abstract
Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian [...] Read more.
Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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