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IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response
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IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 18833

Special Issue Editors

Prof. Dr. Nicola Curtin

E-Mail Website
Guest Editor
Faculty of Medical Sciences, Newcastle University Centre for Cancer, Newcastle upon Tyne NE1 7RU, UK
Interests: DNA damage response: PARP, ATR, CHK1, ATM, DNA-PK; Functional biomarkers of DNA repair
Special Issues, Collections and Topics in MDPI journals
Dr. Helen E. Bryant

E-Mail Website
Guest Editor
Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
Interests: DNA damage response; radiotherapy response; PARP

Special Issue Information

Dear Colleagues,

This Special Issue will comprise selected papers from the proceedings of the 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response (IECC 2021) 1–14 February, 2021, held on sciforum.net, an online platform for hosting scholarly e-conferences and discussion groups.

The focus of this conference is the translation of a basic science understanding of the DNA Damage Response (DDR) and its dysregulation in cancer to its therapeutic exploitation, and is divided into seven sessions, each with an invited keynote speaker and chair and short proffered talks on the following:

  • An overview of targeting DDR dysfunction in cancer;
  • DNA damage cell cycle checkpoints;
  • DNA repair, defects in cancer, and their exploitation;
  • MMR defects, mutator phenotype;
  • SUMO and ubiquitination, and other epigenetic and post-translational mechanisms;
  • Targeting with immune checkpoint inhibitors;
  • The overview and use of biomarkers in clinical trials.

There will also be posters on the above topics.

Selected papers that attract the most interest on the web or that provide a particularly innovative contribution will be selected for publication. These papers will be subjected to peer review and published with the aim of rapid and wide dissemination of research results, developments, and applications. We hope this Conference Series will continue to grow in acceptance and recognition among potential participants, contributors, experts who want to disseminate their latest findings, and readers who seek information on DDR exploitation in cancer.

Prof. Dr. Nicola Curtin
Dr. Helen E. Bryant
Guest Editors

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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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.

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

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13 pages, 4066 KiB  
Article
Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer
by Shihori Tanabe, Sabina Quader, Ryuichi Ono, Horacio Cabral, Kazuhiko Aoyagi, Akihiko Hirose, Hiroshi Yokozaki and Hiroki Sasaki
Cancers 2021, 13(22), 5786; https://doi.org/10.3390/cancers13225786 - 18 Nov 2021
Cited by 8 | Viewed by 2384
Abstract
Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of [...] Read more.
Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT. Full article
(This article belongs to the Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response)
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21 pages, 3655 KiB  
Article
Topological Analysis of γH2AX and MRE11 Clusters Detected by Localization Microscopy during X-ray-Induced DNA Double-Strand Break Repair
by Hannes Hahn, Charlotte Neitzel, Olga Kopečná, Dieter W. Heermann, Martin Falk and Michael Hausmann
Cancers 2021, 13(21), 5561; https://doi.org/10.3390/cancers13215561 - 5 Nov 2021
Cited by 11 | Viewed by 2942
Abstract
DNA double-strand breaks (DSBs), known as the most severe damage in chromatin, were induced in breast cancer cells and normal skin fibroblasts by 2 Gy ionizing photon radiation. In response to DSB induction, phosphorylation of the histone variant H2AX to γH2AX was observed [...] Read more.
DNA double-strand breaks (DSBs), known as the most severe damage in chromatin, were induced in breast cancer cells and normal skin fibroblasts by 2 Gy ionizing photon radiation. In response to DSB induction, phosphorylation of the histone variant H2AX to γH2AX was observed in the form of foci visualized by specific antibodies. By means of super-resolution single-molecule localization microscopy (SMLM), it has been recently shown in a first article about these data that these foci can be separated into clusters of about the same size (diameter ~400 nm). The number of clusters increased with the dose applied and decreased with the repair time. It has also been shown that during the repair period, antibody-labeled MRE11 clusters of about half of the γH2AX cluster diameter were formed inside several γH2AX clusters. MRE11 is part of the MRE11–RAD50–NBS1 (MRN) complex, which is known as a DNA strand resection and broken-end bridging component in homologous recombination repair (HRR) and alternative non-homologous end joining (a-NHEJ). This article is a follow-up of the former ones applying novel procedures of mathematics (topology) and similarity measurements on the data set: to obtain a measure for cluster shape and shape similarities, topological quantifications employing persistent homology were calculated and compared. In addition, based on our findings that γH2AX clusters associated with heterochromatin show a high degree of similarity independently of dose and repair time, these earlier published topological analyses and similarity calculations comparing repair foci within individual cells were extended by topological data averaging (2nd-generation heatmaps) over all cells analyzed at a given repair time point; thereby, the two dimensions (0 and 1) expressed by components and holes were studied separately. Finally, these mean value heatmaps were averaged, in addition. For γH2AX clusters, in both normal fibroblast and MCF-7 cancer cell lines, an increased similarity was found at early time points (up to 60 min) after irradiation for both components and holes of clusters. In contrast, for MRE11, the peak in similarity was found at later time points (2 h up to 48 h) after irradiation. In general, the normal fibroblasts showed quicker phosphorylation of H2AX and recruitment of MRE11 to γH2AX clusters compared to breast cancer cells and a shorter time interval of increased similarity for γH2AX clusters. γH2AX foci and randomly distributed MRE11 molecules naturally occurring in non-irradiated control cells did not show any significant topological similarity. Full article
(This article belongs to the Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response)
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15 pages, 3033 KiB  
Article
RAD50 Loss of Function Variants in the Zinc Hook Domain Associated with Higher Risk of Familial Esophageal Squamous Cell Carcinoma
by Josephine Mun Yee Ko, Shiu Yeung Lam, Lvwen Ning, Annie Wai Yeeng Chai, Lisa Chan Lei, Sheyne Sta Ana Choi, Carissa Wing Yan Wong and Maria Li Lung
Cancers 2021, 13(18), 4715; https://doi.org/10.3390/cancers13184715 - 21 Sep 2021
Cited by 2 | Viewed by 3046
Abstract
Unbiased whole-exome sequencing approaches in familial esophageal squamous cell carcinoma (ESCC) initially prioritized RAD50 as a candidate cancer predisposition gene. The combined study with 3289 Henan individuals from Northern China identified two pathogenic RAD50 protein truncation variants, p.Q672X and a recurrent p.K722fs variant [...] Read more.
Unbiased whole-exome sequencing approaches in familial esophageal squamous cell carcinoma (ESCC) initially prioritized RAD50 as a candidate cancer predisposition gene. The combined study with 3289 Henan individuals from Northern China identified two pathogenic RAD50 protein truncation variants, p.Q672X and a recurrent p.K722fs variant at the zinc hook domain significantly conferring increased familial ESCC risk. Effects of ~10-fold higher familial ESCC risk were observed, when compared to East Asians from the gnomAD database. Functional characterization suggested that the RAD50Q672X mutation contributes a dominant-negative effect in DNA repair of double-stranded breaks. Overexpression of the RAD50Q672X and RAD50L1264F missense mutation also sensitized cell death upon replication stress stimuli induced by formaldehyde treatment and the CHK1 inhibitor, AZD7762. Our study suggested the novel insight of the potential for synthetic lethal therapeutic options for RAD50Q672X and the East-Asian-specific RAD50L1264F variants and CHK1 inhibitors. Our study also suggested the association of RAD50 LOF variants in the zinc hook domain with a higher risk of familial ESCC in Chinese. Full article
(This article belongs to the Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response)
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20 pages, 4104 KiB  
Article
Depletion of DNA Polymerase Theta Inhibits Tumor Growth and Promotes Genome Instability through the cGAS-STING-ISG Pathway in Esophageal Squamous Cell Carcinoma
by Jian Li, Josephine Mun-Yee Ko, Wei Dai, Valen Zhuoyou Yu, Hoi Yan Ng, Jean-Sébastien Hoffmann and Maria Li Lung
Cancers 2021, 13(13), 3204; https://doi.org/10.3390/cancers13133204 - 26 Jun 2021
Cited by 17 | Viewed by 4267
Abstract
Overexpression of the specialized DNA polymerase theta (POLQ) is frequent in breast, colon and lung cancers and has been correlated with unfavorable clinical outcomes. Here, we aimed to determine the importance and functional role of POLQ in esophageal squamous cell carcinoma (ESCC). Integrated [...] Read more.
Overexpression of the specialized DNA polymerase theta (POLQ) is frequent in breast, colon and lung cancers and has been correlated with unfavorable clinical outcomes. Here, we aimed to determine the importance and functional role of POLQ in esophageal squamous cell carcinoma (ESCC). Integrated analysis of four RNA-seq datasets showed POLQ was predominantly upregulated in ESCC tumors. High expression of POLQ was also observed in a cohort of 25 Hong Kong ESCC patients and negatively correlated with ESCC patient survival. POLQ knockout (KO) ESCC cells were sensitized to multiple genotoxic agents. Both rH2AX foci staining and the comet assay indicated a higher level of genomic instability in POLQ-depleted cells. Double KO of POLQ and FANCD2, known to promote POLQ recruitment at sites of damage, significantly impaired cell proliferation both in vitro and in vivo, as compared to either single POLQ or FANCD2 KOs. A significantly increased number of micronuclei was observed in POLQ and/or FANCD2 KO ESCC cells. Loss of POLQ and/or FANCD2 also resulted in the activation of cGAS and upregulation of interferon-stimulated genes (ISGs). Our results suggest that high abundance of POLQ in ESCC contributes to the malignant phenotype through genome instability and activation of the cGAS pathway. Full article
(This article belongs to the Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response)
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Review

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36 pages, 1629 KiB  
Review
Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation
by Jacqueline Nathansen, Felix Meyer, Luise Müller, Marc Schmitz, Kerstin Borgmann and Anna Dubrovska
Cancers 2021, 13(19), 4818; https://doi.org/10.3390/cancers13194818 - 26 Sep 2021
Cited by 25 | Viewed by 4664
Abstract
Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative [...] Read more.
Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets. Full article
(This article belongs to the Special Issue IECC2021: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response)
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