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DNA Damage, DNA Repair, and Cancer
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DNA Damage, DNA Repair, and Cancer

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 (30 June 2022) | Viewed by 18708

Special Issue Editor

Dr. Kazuhiko Kuwahara

E-Mail Website
Guest Editor
Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
Interests: transcription-coupled DNA damage; lymphomagenesis; mRNA export; breast carcinogenesis; antibody engineering

Special Issue Information

Dear Colleagues,

DNA lesions produced by a variety of genotoxic stresses are precisely repaired to avoid the genomic instability which is associated with a high predisposition to cancer development. The occurrence of unrepaired DNA lesions is censored by DNA-damage response (DDR) composed of complex cascades followed by the induction of cell-cycle arrest or apoptosis. As most tumors show impaired DDR, many studies have focused on the understanding of detailed molecular mechanisms in DDR-pathways and/or cancer-related DNA repair defects to reveal the cause of cancers. In addition, this information has provided us new therapeutic targets. Recently, when the germ-line mutations exist in breast cancers, PARP inhibitors offer a new therapeutic option based on the concept of synthetic lethality. Moreover, it is known that various inhibitors targeting molecules associated with DDR are in clinical trials. Comprehensive analyses of canonical and non-canonical DNA repair pathways and the interactions of each molecule defective in various cancers are promising to search for potential therapeutic targets. Therefore, authors are invited to submit original research and review articles that address the physiological, pathophysiological, pharmacological, and epidemiological importance of DDR and/or DNA repair pathways in cancer development.

Topics include, but are not limited to:

  • Involvement of canonical or non-canonical DNA repair pathways in cancer development;
  • Identification of the novel therapeutic targets in DNA repair pathway;
  • Animal models mimicking the development of various human cancers;
  • Pathological significance of aberrantly expressed DNA repair-related molecules in human clinical samples.

Dr. Kazuhiko Kuwahara
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 response
  • DNA repair molecules
  • genome instability
  • cellular senescence
  • animal models
  • DNA Damage, DNA Repair and Cancer

Published Papers (6 papers)

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Research

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17 pages, 19641 KiB  
Article
Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease
by Míriam Gené, Míriam Cuatrecasas, Irene Amat, Jesús Alberto Veiga, María Jesús Fernández Aceñero, Victòria Fusté Chimisana, Jordi Tarragona, Ismael Jurado, Rebeca Fernández-Victoria, Carolina Martínez Ciarpaglini, Cristina Alenda González, Carlos Zac, Pilar Ortega de la Obra, María Teresa Fernández-Figueras, Manel Esteller and Eva Musulen
Int. J. Mol. Sci. 2023, 24(10), 8655; https://doi.org/10.3390/ijms24108655 - 12 May 2023
Cited by 3 | Viewed by 2026
Abstract
Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the “chronic inflammation-dysplasia-cancer” carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, [...] Read more.
Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the “chronic inflammation-dysplasia-cancer” carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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19 pages, 5166 KiB  
Article
Lactate Suppresses Retroviral Transduction in Cervical Epithelial Cells through DNA-PKcs Modulation
by Waldemar Wagner, Katarzyna Sobierajska, Katarzyna Dominika Kania, Edyta Paradowska and Wojciech Michał Ciszewski
Int. J. Mol. Sci. 2021, 22(24), 13194; https://doi.org/10.3390/ijms222413194 - 7 Dec 2021
Cited by 4 | Viewed by 2747
Abstract
Recently, we have shown the molecular basis for lactate sensing by cervical epithelial cells resulting in enhanced DNA repair processes through DNA-PKcs regulation. Interestingly, DNA-PKcs is indispensable for proper retroviral DNA integration in the cell host genome. According to recent findings, the mucosal [...] Read more.
Recently, we have shown the molecular basis for lactate sensing by cervical epithelial cells resulting in enhanced DNA repair processes through DNA-PKcs regulation. Interestingly, DNA-PKcs is indispensable for proper retroviral DNA integration in the cell host genome. According to recent findings, the mucosal epithelium can be efficiently transduced by retroviruses and play a pivotal role in regulating viral release by cervical epithelial cells. This study examined the effects of lactate on lentiviral transduction in cervical cancer cells (HeLa, CaSki, and C33A) and model glioma cell lines (DNA-PKcs proficient and deficient). Our study showed that L- and D-lactate enhanced DNA-PKcs presence in nuclear compartments by between 38 and 63%, which corresponded with decreased lentiviral transduction rates by between 15 and 36%. Changes in DNA-PKcs expression or its inhibition with NU7441 also greatly affected lentiviral transduction efficacy. The stimulation of cells with either HCA1 agonist 3,5-DHBA or HDAC inhibitor sodium butyrate mimicked, in part, the effects of L-lactate. The inhibition of lactate flux by BAY-8002 enhanced DNA-PKcs nuclear localization which translated into diminished lentiviral transduction efficacy. Our study suggests that L- and D-lactate present in the uterine cervix may play a role in the mitigation of viral integration in cervical epithelium and, thus, restrict the viral oncogenic and/or cytopathic potential. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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17 pages, 3147 KiB  
Article
Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer
by Griffin Wright, Manoj Sonavane and Natalie R. Gassman
Int. J. Mol. Sci. 2021, 22(11), 5475; https://doi.org/10.3390/ijms22115475 - 22 May 2021
Cited by 4 | Viewed by 2422
Abstract
Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a [...] Read more.
Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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Review

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25 pages, 5382 KiB  
Review
Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1
by Alexandra L. Zakharenko, Olga A. Luzina, Arina A. Chepanova, Nadezhda S. Dyrkheeva, Nariman F. Salakhutdinov and Olga I. Lavrik
Int. J. Mol. Sci. 2023, 24(6), 5781; https://doi.org/10.3390/ijms24065781 - 17 Mar 2023
Cited by 11 | Viewed by 1726
Abstract
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3′ end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such [...] Read more.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3′ end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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21 pages, 5555 KiB  
Review
DNA Repair Genes as Drug Candidates for Early Breast Cancer Onset in Latin America: A Systematic Review
by Laura Keren Urbina-Jara, Emmanuel Martinez-Ledesma, Augusto Rojas-Martinez, Francisco Ricardo Rodriguez-Recio and Rocio Ortiz-Lopez
Int. J. Mol. Sci. 2021, 22(23), 13030; https://doi.org/10.3390/ijms222313030 - 2 Dec 2021
Viewed by 2360
Abstract
The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC [...] Read more.
The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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16 pages, 693 KiB  
Review
Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy
by Giorgio Valabrega, Giulia Scotto, Valentina Tuninetti, Arianna Pani and Francesco Scaglione
Int. J. Mol. Sci. 2021, 22(8), 4203; https://doi.org/10.3390/ijms22084203 - 19 Apr 2021
Cited by 55 | Viewed by 5480
Abstract
Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. [...] Read more.
Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi. Full article
(This article belongs to the Special Issue DNA Damage, DNA Repair, and Cancer)
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