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DNA Repair in Cancers
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DNA Repair in Cancers

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

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 23313

Special Issue Editor

Dr. Igor Belyaev

E-Mail Website
Guest Editor
Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravska cesta 9, 845 05 Bratislava, Slovakia
Interests: DNA damage and repair; apoptosis; stem cells; ionizing and non-ionizing radiation; electromagnetic fields
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA damage and repair are essential factors which underlie different aspects of cancer, such as induction, promotion, treatment, and risk assessment. DNA double-strand breaks (DSB) represent a most important type of DNA damage, resulting in the formation of chromosomal aberrations, which represent one of the major causes for cancer origination. Thus, the focus of this Special Issue will be DSB. However, types of DNA damage and related issues dealing with mutations, apoptosis, cell cycle, senescence, DNA damage checkpoints, and DNA repair defects in cancer may also be covered in this Special Issue. There are multiple agents, including various chemicals and ionizing radiations, which induce DNA damage and are efficiently used in treatment of cancer through chemo- and radiotherapy. All these aspects are to be covered in the Special Issue, including challenging issues, such as new aspects in mechanisms of DNA repair and induction of DNA damage by non-ionizing radiation and electromagnetic fields.

We would like to invite you to contribute to the Special Issue “DNA Repair in Cancers” of the International Journal of Molecular Sciences (IJMS, https://www.mdpi.com/journal/ijms). This journal has a good impact factor (latest Impact Factor 4.183) and is indexed in Pubmed. Both original studies and reviews are welcome for this Special Issue. If you would like to contribute a review article or original research, it would be greatly appreciated if you could provide a tentative title and a very short abstract of several lines.

Assoc. Prof. Dr. Igor Belyaev
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 double stand breaks
  • DNA repair
  • Cancer
  • Mutation
  • Apoptosis
  • Chromosomal aberrations
  • Radiation

Published Papers (7 papers)

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Research

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19 pages, 2541 KiB  
Article
Evaluation of Calyculin A Effect on γH2AX/53BP1 Focus Formation and Apoptosis in Human Umbilical Cord Blood Lymphocytes
by Lucián Zastko, Anna Račková, Petra Petrovičová, Matúš Durdík, Jakub Míšek, Eva Marková and Igor Belyaev
Int. J. Mol. Sci. 2021, 22(11), 5470; https://doi.org/10.3390/ijms22115470 - 22 May 2021
Cited by 4 | Viewed by 1969
Abstract
Dephosphorylation inhibitor calyculin A (cal A) has been reported to inhibit the disappearance of radiation-induced γH2AX DNA repair foci in human lymphocytes. However, other studies reported no change in the kinetics of γH2AX focus induction and loss in irradiated cells. While apoptosis might [...] Read more.
Dephosphorylation inhibitor calyculin A (cal A) has been reported to inhibit the disappearance of radiation-induced γH2AX DNA repair foci in human lymphocytes. However, other studies reported no change in the kinetics of γH2AX focus induction and loss in irradiated cells. While apoptosis might interplay with the kinetics of focus formation, it was not followed in irradiated cells along with DNA repair foci. Thus, to validate plausible explanations for significant variability in outputs of these studies, we evaluated the effect of cal A (1 and 10 nM) on γH2AX/53BP1 DNA repair foci and apoptosis in irradiated (1, 5, 10, and 100 cGy) human umbilical cord blood lymphocytes (UCBL) using automated fluorescence microscopy and annexin V-FITC/propidium iodide assay/γH2AX pan-staining, respectively. No effect of cal A on γH2AX and colocalized γH2AX/53BP1 foci induced by low doses (≤10 cGy) of γ-rays was observed. Moreover, 10 nM cal A treatment decreased the number of all types of DNA repair foci induced by 100 cGy irradiation. 10 nM cal A treatment induced apoptosis already at 2 h of treatment, independently from the delivered dose. Apoptosis was also detected in UCBL treated with lower cal A concentration, 1 nM, at longer cell incubation, 20 and 44 h. Our data suggest that apoptosis triggered by cal A in UCBL may underlie the failure of cal A to maintain radiation-induced γH2AX foci. All DSB molecular markers used in this study responded linearly to low-dose irradiation. Therefore, their combination may represent a strong biodosimetry tool for estimation of radiation response to low doses. Assessment of colocalized γH2AX/53BP1 improved the threshold of low dose detection. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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25 pages, 10933 KiB  
Article
Elucidation of the Clustered Nano-Architecture of Radiation-Induced DNA Damage Sites and Surrounding Chromatin in Cancer Cells: A Single Molecule Localization Microscopy Approach
by Michael Hausmann, Martin Falk, Charlotte Neitzel, Andreas Hofmann, Abin Biswas, Theresa Gier, Iva Falkova, Dieter W. Heermann and Georg Hildenbrand
Int. J. Mol. Sci. 2021, 22(7), 3636; https://doi.org/10.3390/ijms22073636 - 31 Mar 2021
Cited by 12 | Viewed by 2628
Abstract
In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a “double-edged sword”—it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or [...] Read more.
In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a “double-edged sword”—it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or even initiate carcinogenesis in the normal irradiated tissue. Individualized radiotherapy would reduce these risks and boost the treatment, but its development requires a deep understanding of DNA damage and repair processes and the corresponding control mechanisms. DNA double strand breaks (DSBs) and their repair play a critical role in the cellular response to radiation. In previous years, it has become apparent that, beyond genetic and epigenetic determinants, the structural aspects of damaged chromatin (i.e., not only of DSBs themselves but also of the whole damage-surrounding chromatin domains) form another layer of complex DSB regulation. In the present article, we summarize the application of super-resolution single molecule localization microscopy (SMLM) for investigations of these structural aspects with emphasis on the relationship between the nano-architecture of radiation-induced repair foci (IRIFs), represented here by γH2AX foci, and their chromatin environment. Using irradiated HeLa cell cultures as an example, we show repair-dependent rearrangements of damaged chromatin and analyze the architecture of γH2AX repair clusters according to topological similarities. Although HeLa cells are known to have highly aberrant genomes, the topological similarity of γH2AX was high, indicating a functional, presumptively genome type-independent relevance of structural aspects in DSB repair. Remarkably, nano-scaled chromatin rearrangements during repair depended both on the chromatin domain type and the treatment. Based on these results, we demonstrate how the nano-architecture and topology of IRIFs and chromatin can be determined, point to the methodological relevance of SMLM, and discuss the consequences of the observed phenomena for the DSB repair network regulation or, for instance, radiation treatment outcomes. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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17 pages, 2516 KiB  
Article
Differential DNA Methylation in Prostate Tumors from Puerto Rican Men
by Gilberto Ruiz-Deya, Jaime Matta, Jarline Encarnación-Medina, Carmen Ortiz-Sanchéz, Julie Dutil, Ryan Putney, Anders Berglund, Jasreman Dhillon, Youngchul Kim and Jong Y. Park
Int. J. Mol. Sci. 2021, 22(2), 733; https://doi.org/10.3390/ijms22020733 - 13 Jan 2021
Cited by 3 | Viewed by 2728
Abstract
In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes [...] Read more.
In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive (n = 11) and indolent (n = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including AOX1 were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes (RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, and GABRQ) and 11 hypomethylated genes (COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12) were identified. Two significant differentially methylated DNA repair genes, JMJD1C and RNF169, were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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10 pages, 1515 KiB  
Communication
Low Repair Capacity of DNA Double-Strand Breaks Induced by Laser-Driven Ultrashort Electron Beams in Cancer Cells
by Nelly Babayan, Natalia Vorobyeva, Bagrat Grigoryan, Anna Grekhova, Margarita Pustovalova, Sofya Rodneva, Yuriy Fedotov, Gohar Tsakanova, Rouben Aroutiounian and Andreyan Osipov
Int. J. Mol. Sci. 2020, 21(24), 9488; https://doi.org/10.3390/ijms21249488 - 14 Dec 2020
Cited by 17 | Viewed by 2879
Abstract
Laser-driven accelerators allow to generate ultrashort (from femto- to picoseconds) high peak dose-rate (up to tens of GGy/s) accelerated particle beams. However, the radiobiological effects of ultrashort pulsed irradiation are still poorly studied. The aim of this work was to compare the formation [...] Read more.
Laser-driven accelerators allow to generate ultrashort (from femto- to picoseconds) high peak dose-rate (up to tens of GGy/s) accelerated particle beams. However, the radiobiological effects of ultrashort pulsed irradiation are still poorly studied. The aim of this work was to compare the formation and elimination of γH2AX and 53BP1 foci (well known markers for DNA double-strand breaks (DSBs)) in Hela cells exposed to ultrashort pulsed electron beams generated by Advanced Research Electron Accelerator Laboratory (AREAL) accelerator (electron energy 3.6 MeV, pulse duration 450 fs, pulse repetition rates 2 or 20 Hz) and quasi-continuous radiation generated by Varian accelerator (electron energy 4 MeV) at doses of 250–1000 mGy. Additionally, a study on the dose–response relationships of changes in the number of residual γH2AX foci in HeLa and A549 cells 24 h after irradiation at doses of 500–10,000 mGy were performed. We found no statistically significant differences in γH2AX and 53BP1 foci yields at 1 h after exposure to 2 Hz ultrashort pulse vs. quasi-continuous radiations. In contrast, 20 Hz ultrashort pulse irradiation resulted in 1.27-fold higher foci yields as compared to the quasi-continuous one. After 24 h of pulse irradiation at doses of 500–10,000 mGy the number of residual γH2AX foci in Hela and A549 cells was 1.7–2.9 times higher compared to that of quasi-continuous irradiation. Overall, the obtained results suggest the slower repair rate for DSBs induced by ultrashort pulse irradiation in comparison to DSBs induced by quasi-continuous irradiation. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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Review

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12 pages, 590 KiB  
Review
Effect of Sepatronium Bromide (YM-155) on DNA Double-Strand Breaks Repair in Cancer Cells
by Dusana Majera and Martin Mistrik
Int. J. Mol. Sci. 2020, 21(24), 9431; https://doi.org/10.3390/ijms21249431 - 11 Dec 2020
Cited by 5 | Viewed by 2698
Abstract
Survivin, as an antiapoptotic protein often overexpressed in cancer cells, is a logical target for potential cancer treatment. By overexpressing survivin, cancer cells can avoid apoptotic cell death and often become resistant to treatments, representing a significant obstacle in modern oncology. A survivin [...] Read more.
Survivin, as an antiapoptotic protein often overexpressed in cancer cells, is a logical target for potential cancer treatment. By overexpressing survivin, cancer cells can avoid apoptotic cell death and often become resistant to treatments, representing a significant obstacle in modern oncology. A survivin suppressor, an imidazolium-based compound known as YM-155, is nowadays studied as an attractive anticancer agent. Although survivin suppression by YM-155 is evident, researchers started to report that YM-155 is also an inducer of DNA damage introducing yet another anticancer mechanism of this drug. Moreover, the concentrations of YM-155 for DNA damage induction seems to be far lower than those needed for survivin inhibition. Understanding the molecular mechanism of action of YM-155 is of vital importance for modern personalized medicine involving the selection of responsive patients and possible treatment combinations. This review focuses mainly on the documented effects of YM-155 on DNA damage signaling pathways. It summarizes up to date literature, and it outlines the molecular mechanism of YM-155 action in the context of the DNA damage field. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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22 pages, 383 KiB  
Review
Targeting DNA Damage Response in Prostate and Breast Cancer
by Antje M. Wengner, Arne Scholz and Bernard Haendler
Int. J. Mol. Sci. 2020, 21(21), 8273; https://doi.org/10.3390/ijms21218273 - 04 Nov 2020
Cited by 50 | Viewed by 6044
Abstract
Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. [...] Read more.
Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia–telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
17 pages, 616 KiB  
Review
Targeting DNA Repair Pathways in Hematological Malignancies
by Jehad F. Alhmoud, Ayman G. Mustafa and Mohammed Imad Malki
Int. J. Mol. Sci. 2020, 21(19), 7365; https://doi.org/10.3390/ijms21197365 - 06 Oct 2020
Cited by 9 | Viewed by 3122
Abstract
DNA repair plays an essential role in protecting cells that are repeatedly exposed to endogenous or exogenous insults that can induce varying degrees of DNA damage. Any defect in DNA repair mechanisms results in multiple genomic changes that ultimately may result in mutation, [...] Read more.
DNA repair plays an essential role in protecting cells that are repeatedly exposed to endogenous or exogenous insults that can induce varying degrees of DNA damage. Any defect in DNA repair mechanisms results in multiple genomic changes that ultimately may result in mutation, tumor growth, and/or cell apoptosis. Furthermore, impaired repair mechanisms can also lead to genomic instability, which can initiate tumorigenesis and development of hematological malignancy. This review discusses recent findings and highlights the importance of DNA repair components and the impact of their aberrations on hematological malignancies. Full article
(This article belongs to the Special Issue DNA Repair in Cancers)
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