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Cells
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DNA Damage and DNA Repair: What’s New in Biology and...
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DNA Damage and DNA Repair: What’s New in Biology and Cancer Therapeutics?

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 8056

Special Issue Editor

Prof. Dr. Srinivasan Madhusudan

E-Mail Website
Guest Editor
Professor of Medical Oncology, Translational DNA Repair Group, Nottingham Biodiscovery Institute, School of Medicine, Nottingham University Hospitals, University Park, Nottingham NG7 3RD, UK
Interests: DNA repair; synthetic lethality; precision oncology; breast cancer; ovarian cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. A large body of evidence suggests that impaired DNA repair capacity promotes cancer development. Interestingly, upregulation of DDR can lead to chemotherapy and/or radiotherapy resistance. Recent advances in DNA repair have led to several translational investigations, resulting in clinically viable precision oncology strategies through the use of synthetic lethality, such as the use of PARP inhibitors in breast, ovarian, pancreatic and prostate cancers.  Whilst the clinical use of PARP inhibitors has expanded our knowledge on the topic, it is clear that the emergence of resistance is a considerable clinical problem.  Therefore, the search for additional DDR-directed drug targets and novel synthetic lethality approaches is an area of recent research. 

The Special Issue will focus on our current understanding of DNA repair pathways in humans and their exploitation for precision oncology therapeutics in cancer. 

Prof. Dr. Srinivasan Madhusudan
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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.

Keywords

  • DNA repair pathways
  • synthetic lethality
  • precision oncology

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Published Papers (4 papers)

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Research

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17 pages, 2961 KiB  
Article
ATM/ATR Phosphorylation of CtIP on Its Conserved Sae2-like Domain Is Required for Genotoxin-Induced DNA Resection but Dispensable for Animal Development
by Foon Wu-Baer, Madeline Wong, Lydia Tschoe, Chyuan-Sheng Lin, Wenxia Jiang, Shan Zha and Richard Baer
Cells 2023, 12(23), 2762; https://doi.org/10.3390/cells12232762 - 4 Dec 2023
Viewed by 1672
Abstract
Homology-directed repair (HDR) of double-strand DNA breaks (DSBs) is dependent on enzymatic resection of DNA ends by the Mre11/Rad50/Nbs1 complex. DNA resection is triggered by the CtIP/Sae2 protein, which allosterically promotes Mre11-mediated endonuclease DNA cleavage at a position internal to the DSB. Although [...] Read more.
Homology-directed repair (HDR) of double-strand DNA breaks (DSBs) is dependent on enzymatic resection of DNA ends by the Mre11/Rad50/Nbs1 complex. DNA resection is triggered by the CtIP/Sae2 protein, which allosterically promotes Mre11-mediated endonuclease DNA cleavage at a position internal to the DSB. Although the mechanics of resection, including the initial endonucleolytic step, are largely conserved in eucaryotes, CtIP and its functional counterpart in Saccharomyces cerevisiae (Sae2) share only a modest stretch of amino acid homology. Nonetheless, this stretch contains two highly conserved phosphorylation sites for cyclin-dependent kinases (T843 in mouse) and the damage-induced ATM/ATR kinases (T855 in mouse), both of which are required for DNA resection. To explore the function of ATM/ATR phosphorylation at Ctip-T855, we generated and analyzed mice expressing the Ctip-T855A mutant. Surprisingly, unlike Ctip-null mice and Ctip-T843A-expressing mice, both of which undergo embryonic lethality, homozygous CtipT855A/T855A mice develop normally. Nonetheless, they are hypersensitive to ionizing radiation, and CtipT855A/T855A mouse embryo fibroblasts from these mice display marked defects in DNA resection, chromosomal stability, and HDR-mediated repair of DSBs. Thus, although ATM/ATR phosphorylation of CtIP-T855 is not required for normal animal development, it enhances CtIP-mediated DNA resection in response to acute stress, such as genotoxin exposure. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair: What’s New in Biology and Cancer Therapeutics?)
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17 pages, 8248 KiB  
Article
Altered Regulation of the Glucose Transporter GLUT3 in PRDX1 Null Cells Caused Hypersensitivity to Arsenite
by Reem Ali, Abdallah Alhaj Sulaiman, Bushra Memon, Singdhendubala Pradhan, Mashael Algethami, Mustapha Aouida, Gordon McKay, Srinivasan Madhusudan, Essam M. Abdelalim and Dindial Ramotar
Cells 2023, 12(23), 2682; https://doi.org/10.3390/cells12232682 - 22 Nov 2023
Cited by 1 | Viewed by 1722
Abstract
Targeting tumour metabolism through glucose transporters is an attractive approach. However, the role these transporters play through interaction with other signalling proteins is not yet defined. The glucose transporter SLC2A3 (GLUT3) is a member of the solute carrier transporter proteins. GLUT3 has a [...] Read more.
Targeting tumour metabolism through glucose transporters is an attractive approach. However, the role these transporters play through interaction with other signalling proteins is not yet defined. The glucose transporter SLC2A3 (GLUT3) is a member of the solute carrier transporter proteins. GLUT3 has a high affinity for D-glucose and regulates glucose uptake in the neurons, as well as other tissues. Herein, we show that GLUT3 is involved in the uptake of arsenite, and its level is regulated by peroxiredoxin 1 (PRDX1). In the absence of PRDX1, GLUT3 mRNA and protein expression levels are low, but they are increased upon arsenite treatment, correlating with an increased uptake of glucose. The downregulation of GLUT3 by siRNA or deletion of the gene by CRISPR cas-9 confers resistance to arsenite. Additionally, the overexpression of GLUT3 sensitises the cells to arsenite. We further show that GLUT3 interacts with PRDX1, and it forms nuclear foci, which are redistributed upon arsenite exposure, as revealed by immunofluorescence analysis. We propose that GLUT3 plays a role in mediating the uptake of arsenite into cells, and its homeostatic and redox states are tightly regulated by PRDX1. As such, GLUT3 and PRDX1 are likely to be novel targets for arsenite-based cancer therapy. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair: What’s New in Biology and Cancer Therapeutics?)
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14 pages, 5620 KiB  
Article
SMYD3 Modulates AMPK-mTOR Signaling Balance in Cancer Cell Response to DNA Damage
by Martina Lepore Signorile, Paola Sanese, Elisabetta Di Nicola, Candida Fasano, Giovanna Forte, Katia De Marco, Vittoria Disciglio, Marialaura Latrofa, Antonino Pantaleo, Greta Varchi, Alberto Del Rio, Valentina Grossi and Cristiano Simone
Cells 2023, 12(22), 2644; https://doi.org/10.3390/cells12222644 - 17 Nov 2023
Cited by 5 | Viewed by 1646
Abstract
Cells respond to DNA damage by activating a complex array of signaling networks, which include the AMPK and mTOR pathways. After DNA double-strand breakage, ATM, a core component of the DNA repair system, activates the AMPK-TSC2 pathway, leading to the inhibition of the [...] Read more.
Cells respond to DNA damage by activating a complex array of signaling networks, which include the AMPK and mTOR pathways. After DNA double-strand breakage, ATM, a core component of the DNA repair system, activates the AMPK-TSC2 pathway, leading to the inhibition of the mTOR cascade. Recently, we showed that both AMPK and mTOR interact with SMYD3, a methyltransferase involved in DNA damage response. In this study, through extensive molecular characterization of gastrointestinal and breast cancer cells, we found that SMYD3 is part of a multiprotein complex that is involved in DNA damage response and also comprises AMPK and mTOR. In particular, upon exposure to the double-strand break-inducing agent neocarzinostatin, SMYD3 pharmacological inhibition suppressed AMPK cascade activation and thereby promoted the mTOR pathway, which reveals the central role played by SMYD3 in the modulation of AMPK-mTOR signaling balance during cancer cell response to DNA double-strand breaks. Moreover, we found that SMYD3 can methylate AMPK at the evolutionarily conserved residues Lys411 and Lys424. Overall, our data revealed that SMYD3 can act as a bridge between the AMPK and mTOR pathways upon neocarzinostatin-induced DNA damage in gastrointestinal and breast cancer cells. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair: What’s New in Biology and Cancer Therapeutics?)
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Review

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31 pages, 3860 KiB  
Review
Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons
by Matilde Clarissa Malfatti, Alessia Bellina, Giulia Antoniali and Gianluca Tell
Cells 2023, 12(14), 1895; https://doi.org/10.3390/cells12141895 - 20 Jul 2023
Cited by 13 | Viewed by 2368
Abstract
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in [...] Read more.
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair: What’s New in Biology and Cancer Therapeutics?)
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