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DNA Damage, Genomic Instability and Human Diseases

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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 October 2022) | Viewed by 12949

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Special Issue Editor

Dr. Lubos Cipak

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Guest Editor

Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
Interests: maintenance of genome stability; post-translational modification; protein kinase; splicing; helicase
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is well known that protecting of genome is important for each organism because DNA alterations such as mutations and chromosomal aberrations can lead to tumorigenesis, development of various diseases, or cell death. Therefore, cells have evolved multiple mechanisms to detect and repair DNA breaks, mismatches and mutations of damaged or incompletely replicated DNA to secure the integrity of the genome.

In this Special Issue, we welcome reviews, original research articles and communications that advance our understanding of all aspects of mechanisms participating in genome maintenance, with a special focus on better understanding of the regulatory mechanisms of DNA repair pathways, crosstalk between different DNA repair pathways and coordination of DNA repair complexes with DNA replication or RNA transcription machinery.

Dr. Lubos Cipak
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 damage
DNA repair
DNA damage response
genomic instability
DNA replication
DNA damage checkpoint

Published Papers (6 papers)

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Research

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22 pages, 4520 KiB

Open AccessArticle

Unraveling the Structural Changes in the DNA-Binding Region of Tumor Protein p53 (TP53) upon Hotspot Mutation p53 Arg248 by Comparative Computational Approach

by Ambritha Balasundaram and C. George Priya Doss

Int. J. Mol. Sci. 2022, 23(24), 15499; https://doi.org/10.3390/ijms232415499 - 07 Dec 2022

Cited by 2 | Viewed by 2067

Abstract

The vital tissue homeostasis regulator p53 forms a tetramer when it binds to DNA and regulates the genes that mediate essential biological processes such as cell-cycle arrest, senescence, DNA repair, and apoptosis. Missense mutations in the core DNA-binding domain (109–292) simultaneously cause the loss of p53 tumor suppressor function and accumulation of the mutant p53 proteins that are carcinogenic. The most common p53 hotspot mutation at codon 248 in the DNA-binding region, where arginine (R) is substituted by tryptophan (W), glycine (G), leucine (L), proline (P), and glutamine (Q), is reported in various cancers. However, it is unclear how the p53 Arg248 mutation with distinct amino acid substitution affects the structure, function, and DNA binding affinity. Here, we characterized the pathogenicity and protein stability of p53 hotspot mutations at codon 248 using computational tools PredictSNP, Align GVGD, HOPE, ConSurf, and iStable. We found R248W, R248G, and R248P mutations highly deleterious and destabilizing. Further, we subjected all five R248 mutant-p53–DNA and wt-p53–DNA complexes to molecular dynamics simulation to investigate the structural stability and DNA binding affinity. From the MD simulation analysis, we observed increased RMSD, RMSF, and Rg values and decreased protein–DNA intermolecular hydrogen bonds in the R248-p53–DNA than the wt-p53–DNA complexes. Likewise, due to high SASA values, we observed the shrinkage of proteins in R248W, R248G, and R248P mutant-p53–DNA complexes. Compared to other mutant p53–DNA complexes, the R248W, R248G, and R248P mutant-p53–DNA complexes showed more structural alteration. MM-PBSA analysis showed decreased binding energies with DNA in all five R248-p53–DNA mutants than the wt-p53–DNA complexes. Henceforth, we conclude that the amino acid substitution of Arginine with the other five amino acids at codon 248 reduces the p53 protein’s affinity for DNA and may disrupt cell division, resulting in a gain of p53 function. The proposed study influences the development of rationally designed molecular-targeted treatments that improve p53-based therapeutic outcomes in cancer. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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12 pages, 2673 KiB

Open AccessArticle

Influence of the Photodegradation of Azathioprine on DNA and Cells

by Mihaela-Cristina Bunea, Victor-Constantin Diculescu, Monica Enculescu, Daniela Oprea and Teodor Adrian Enache

Int. J. Mol. Sci. 2022, 23(22), 14438; https://doi.org/10.3390/ijms232214438 - 20 Nov 2022

Cited by 1 | Viewed by 1312

Abstract

Azathioprine (AZA) is a pharmacologic immunosuppressive agent administrated in various conditions such as autoimmune disease or to prevent the rejection of organ transplantation. The mechanism of action is based on its biologically active metabolite 6-mercaptopurine (6-MP), which is converted, among others, into thioguanine nucleotides capable of incorporating into replicating DNA, which may act as a strong UV chromophore and trigger DNA oxidation. The interaction between azathioprine and DNA, before and after exposure to solar simulator radiation, was investigated using UV–vis spectrometry and differential pulse voltammetry at a glassy carbon electrode. The results indicated that the interaction of AZA with UV radiation was pH-dependent and occurred with the formation of several metabolites, which induced oxidative damage in DNA, and the formation of DNA-metabolite adducts. Moreover, the viability assays obtained for the L929 cell culture showed that both azathioprine and degraded azathioprine induced a decrease in cell proliferation. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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18 pages, 3435 KiB

Open AccessArticle

Genes Possessing the Most Frequent DNA DSBs Are Highly Associated with Development and Cancers, and Essentially Overlap with the rDNA-Contacting Genes

by Nickolai A. Tchurikov, Ildar R. Alembekov, Elena S. Klushevskaya, Antonina N. Kretova, Ann M. Keremet, Anastasia E. Sidorova, Polina B. Meilakh, Vladimir R. Chechetkin, Galina I. Kravatskaya and Yuri V. Kravatsky

Int. J. Mol. Sci. 2022, 23(13), 7201; https://doi.org/10.3390/ijms23137201 - 28 Jun 2022

Cited by 2 | Viewed by 2032

Abstract

Double-strand DNA breakes (DSBs) are the most deleterious and widespread examples of DNA damage. They inevitably originate from endogenous mechanisms in the course of transcription, replication, and recombination, as well as from different exogenous factors. If not properly repaired, DSBs result in cell death or diseases. Genome-wide analysis of DSBs has revealed the numerous endogenous DSBs in human chromosomes. However, until now, it has not been clear what kind of genes are preferentially subjected to breakage. We performed a genetic and epigenetic analysis of the most frequent DSBs in HEK293T cells. Here, we show that they predominantly occur in the active genes controlling differentiation, development, and morphogenesis. These genes are highly associated with cancers and other diseases. About one-third of the genes possessing frequent DSBs correspond to rDNA-contacting genes. Our data suggest that a specific set of active genes controlling morphogenesis are the main targets of DNA breakage in human cells, although there is a specific set of silent genes controlling metabolism that also are enriched in DSBs. We detected this enrichment by different activators and repressors of transcription at DSB target sites, as well breakage at promoters. We propose that both active transcription and silencing of genes give a propensity for DNA breakage. These results have implications for medicine and gene therapy. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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21 pages, 5020 KiB

Open AccessArticle

Genomic Analysis Made It Possible to Identify Gene-Driver Alterations Covering the Time Window between Diagnosis of Neuroblastoma 4S and the Progression to Stage 4

by Marzia Ognibene, Patrizia De Marco, Stefano Parodi, Mariaclaudia Meli, Andrea Di Cataldo, Federico Zara and Annalisa Pezzolo

Int. J. Mol. Sci. 2022, 23(12), 6513; https://doi.org/10.3390/ijms23126513 - 10 Jun 2022

Cited by 6 | Viewed by 1470

Abstract

Neuroblastoma (NB) is a tumor of the developing sympathetic nervous system. Despite recent advances in understanding the complexity of NB, the mechanisms that determine its regression or progression are still largely unknown. Stage 4S NB is characterized by a favorable course of disease and often by spontaneous regression, while progression to true stage 4 is a very rare event. Here, we focused on genomic analysis of an NB case that progressed from stage 4S to stage 4 with a very poor outcome. Array-comparative genomic hybridization (a-CGH) on tumor-tissue DNA, and whole-exome sequencing (WES) on exosomes DNA derived from plasma collected at the onset and at the tumor progression, pointed out relevant genetic changes that can explain this clinical worsening. The combination of a-CGH and WES data allowed for the identification iof somatic copy number aberrations and single-nucleotide variants in genes known to be responsible for aggressive NB. KLRB1, MAPK3 and FANCA genes, which were lost at the time of progression, were studied for their possible role in this event by analyzing in silico the impact of their expression on the outcome of 786 NB patients. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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Review

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15 pages, 1176 KiB

Open AccessReview

Molecular Link between DNA Damage Response and Microtubule Dynamics

by Jung Min Kim

Int. J. Mol. Sci. 2022, 23(13), 6986; https://doi.org/10.3390/ijms23136986 - 23 Jun 2022

Cited by 10 | Viewed by 2542

Abstract

Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years, it has become evident that microtubule networks play a role in genome maintenance during interphase. In this review, we highlight recent advances in understanding the role of microtubule dynamics in DNA damage response and repair. We first describe how DNA damage checkpoints regulate microtubule organization and stability. We then highlight how microtubule networks are involved in the nuclear remodeling following DNA damage, which leads to changes in chromosome organization. Lastly, we discuss how microtubule dynamics participate in the mobility of damaged DNA and promote consequent DNA repair. Together, the literature indicates the importance of microtubule dynamics in genome organization and stability during interphase. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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18 pages, 742 KiB

Open AccessReview

The Interplay of Cohesin and RNA Processing Factors: The Impact of Their Alterations on Genome Stability

by Michaela Osadska, Tomas Selicky, Miroslava Kretova, Jan Jurcik, Barbara Sivakova, Ingrid Cipakova and Lubos Cipak

Int. J. Mol. Sci. 2022, 23(7), 3939; https://doi.org/10.3390/ijms23073939 - 01 Apr 2022

Cited by 1 | Viewed by 2463

Abstract

Cohesin, a multi-subunit protein complex, plays important roles in sister chromatid cohesion, DNA replication, chromatin organization, gene expression, transcription regulation, and the recombination or repair of DNA damage. Recently, several studies suggested that the functions of cohesin rely not only on cohesin-related protein–protein interactions, their post-translational modifications or specific DNA modifications, but that some RNA processing factors also play an important role in the regulation of cohesin functions. Therefore, the mutations and changes in the expression of cohesin subunits or alterations in the interactions between cohesin and RNA processing factors have been shown to have an impact on cohesion, the fidelity of chromosome segregation and, ultimately, on genome stability. In this review, we provide an overview of the cohesin complex and its role in chromosome segregation, highlight the causes and consequences of mutations and changes in the expression of cohesin subunits, and discuss the RNA processing factors that participate in the regulation of the processes involved in chromosome segregation. Overall, an understanding of the molecular determinants of the interplay between cohesin and RNA processing factors might help us to better understand the molecular mechanisms ensuring the integrity of the genome. Full article

(This article belongs to the Special Issue DNA Damage, Genomic Instability and Human Diseases)

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