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DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives

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 April 2024) | Viewed by 19234

Special Issue Editors

Dr. Dana Jurkovičová

E-Mail Website
Guest Editor
Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
Interests: cancer; genetics; epigenetics; DNA damage and repair; mitochondria; therapy resistance; intracellular signaling; biomarkers; targeted therapy
Dr. Ana Cristina Gonçalves

E-Mail Website
Guest Editor
Faculty of Medicine, Laboratory of Oncobiology and Hematology, Institute for Clinical and Biomedical Research (iCBR)—Area of Environment Genetics and Oncobiology (CIMAGO), University of Coimbra, 3000-548 Coimbra, Portugal
Interests: hematologic diseases; oncobiology; oncogenetics/epigenetics; nutrition; drug resistance; DNA damage repair; cancer metabolism; targeted therapies; translational research; personalized oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA damage response (DDR) plays a crucial role in genome integrity preservation. Changes in DNA damage signaling pathways, DNA repair, and DNA recombination, among other mechanisms, can potentially lead to genomic instability, increase susceptibility to cancer, and influence cancer treatment. Genome instability is a well-established hallmark of cancer, also showing a role in tumor sensitivity and resistance to cancer therapy (including chemotherapy and radiation). Since genome instability, mutation burden, and DNA repair efficiency in cancer cells may have prognostic and predictive value, they also provide a portfolio of new molecular targets and treatment strategies in cancer. The clinical success of PARP inhibitors as a personalized treatment of cancers with defective homologous recombination repair highlights the role of DNA repair pathways.

We invite researchers to submit research and review articles addressing various issues DNA repair in cancer, including but not limited to the following topics:

  • DNA damage and repair as mechanisms of carcinogenesis
  • DDR in cancer biology
  • Role of DNA damage and repair in cancer diagnosis and prognosis
  • DNA repair as a molecular target and therapeutic option in cancer

Dr. Dana Jurkovičová
Dr. Ana Cristina Gonçalves
Guest Editors

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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.

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Keywords

  • DNA damage and repair
  • genomic instability
  • cancer therapy
  • cancer resistance
  • biomarkers

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Published Papers (7 papers)

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Research

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15 pages, 3369 KiB  
Article
CellTool: An Open-Source Software Combining Bio-Image Analysis and Mathematical Modeling for the Study of DNA Repair Dynamics
by Georgi Danovski, Teodora Dyankova-Danovska, Rumen Stamatov, Radoslav Aleksandrov, Petar-Bogomil Kanev and Stoyno Stoynov
Int. J. Mol. Sci. 2023, 24(23), 16784; https://doi.org/10.3390/ijms242316784 - 26 Nov 2023
Cited by 5 | Viewed by 1509
Abstract
Elucidating the dynamics of DNA repair proteins is essential to understanding the mechanisms that preserve genomic stability and prevent carcinogenesis. However, the measurement and modeling of protein dynamics at DNA lesions via currently available image analysis tools is cumbersome. Therefore, we developed CellTool—a [...] Read more.
Elucidating the dynamics of DNA repair proteins is essential to understanding the mechanisms that preserve genomic stability and prevent carcinogenesis. However, the measurement and modeling of protein dynamics at DNA lesions via currently available image analysis tools is cumbersome. Therefore, we developed CellTool—a stand-alone open-source software with a graphical user interface for the analysis of time-lapse microscopy images. It combines data management, image processing, mathematical modeling, and graphical presentation of data in a single package. Multiple image filters, segmentation, and particle tracking algorithms, combined with direct visualization of the obtained results, make CellTool an ideal application for the comprehensive analysis of DNA repair protein dynamics. This software enables the fitting of obtained kinetic data to predefined or custom mathematical models. Importantly, CellTool provides a platform for easy implementation of custom image analysis packages written in a variety of programing languages. Using CellTool, we demonstrate that the ALKB homolog 2 (ALKBH2) demethylase is excluded from DNA damage sites despite recruitment of its putative interaction partner proliferating cell nuclear antigen (PCNA). Further, CellTool facilitates the straightforward fluorescence recovery after photobleaching (FRAP) analysis of BRCA1 associated RING domain 1 (BARD1) exchange at complex DNA lesions. In summary, the software presented herein enables the time-efficient analysis of a wide range of time-lapse microscopy experiments through a user-friendly interface. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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13 pages, 3121 KiB  
Article
HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells
by Roberta Gonnella, Andrea Arena, Roberta Zarrella, Maria Saveria Gilardini Montani, Roberta Santarelli and Mara Cirone
Int. J. Mol. Sci. 2023, 24(4), 3933; https://doi.org/10.3390/ijms24043933 - 15 Feb 2023
Cited by 6 | Viewed by 1546
Abstract
Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma, against which current therapies usually fail. In the present study, we show that targeting HSPs, such as HSP27, HSP70 and HSP90, could be an efficient strategy to reduce PEL cell survival, as [...] Read more.
Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma, against which current therapies usually fail. In the present study, we show that targeting HSPs, such as HSP27, HSP70 and HSP90, could be an efficient strategy to reduce PEL cell survival, as it induces strong DNA damage, which correlated with an impairment of DDR. Moreover, as HSP27, HSP70 and HSP90 cross talk with STAT3, their inhibition results in STAT3 de-phosphorylation and. On the other hand, the inhibition of STAT3 may downregulate these HSPs. These findings suggest that targeting HSPs has important implications in cancer therapy, as it can reduce the release of cytokines by PEL cells, which, besides affecting their own survival, could negatively influence anti-cancer immune response. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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12 pages, 303 KiB  
Article
Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients
by Giorgia Gurioli, Gianluca Tedaldi, Alberto Farolfi, Elisabetta Petracci, Claudia Casanova, Giuseppe Comerci, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Daniele Calistri, Valentina Zampiga, Ilaria Cangini, Eugenio Fonzi, Alessandra Virga, Davide Tassinari, Marta Rosati, Paola Ulivi and Ugo De Giorgi
Int. J. Mol. Sci. 2022, 23(24), 15789; https://doi.org/10.3390/ijms232415789 - 13 Dec 2022
Cited by 3 | Viewed by 1798
Abstract
BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations [...] Read more.
BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)

Review

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13 pages, 486 KiB  
Review
Homologous Recombination Deficiency (HRD) in Cutaneous Oncology
by Favour A. Akinjiyan, Renee Morecroft, Jordan Phillipps, Tolulope Adeyelu, Andrew Elliott, Soo J. Park, Omar H. Butt, Alice Y. Zhou and George Ansstas
Int. J. Mol. Sci. 2023, 24(13), 10771; https://doi.org/10.3390/ijms241310771 - 28 Jun 2023
Cited by 1 | Viewed by 2583
Abstract
Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair [...] Read more.
Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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22 pages, 1193 KiB  
Review
The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers
by Hiu Tang, Sanat Kulkarni, Christina Peters, Jasper Eddison, Maryam Al-Ani and Srinivasan Madhusudan
Int. J. Mol. Sci. 2023, 24(8), 7293; https://doi.org/10.3390/ijms24087293 - 14 Apr 2023
Cited by 7 | Viewed by 1975
Abstract
Survival outcomes for patients with advanced ovarian cancer remain poor despite advances in chemotherapy and surgery. Platinum-based systemic chemotherapy can result in a response rate of up to 80%, but most patients will have recurrence and die from the disease. Recently, the DNA-repair-directed [...] Read more.
Survival outcomes for patients with advanced ovarian cancer remain poor despite advances in chemotherapy and surgery. Platinum-based systemic chemotherapy can result in a response rate of up to 80%, but most patients will have recurrence and die from the disease. Recently, the DNA-repair-directed precision oncology strategy has generated hope for patients. The clinical use of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA germ-line-deficient and/or platinum-sensitive epithelial ovarian cancers has improved survival. However, the emergence of resistance is an ongoing clinical challenge. Here, we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in epithelial ovarian cancers. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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23 pages, 970 KiB  
Review
How Do Plants Cope with DNA Damage? A Concise Review on the DDR Pathway in Plants
by Miriam Szurman-Zubrzycka, Paulina Jędrzejek and Iwona Szarejko
Int. J. Mol. Sci. 2023, 24(3), 2404; https://doi.org/10.3390/ijms24032404 - 26 Jan 2023
Cited by 21 | Viewed by 3328
Abstract
DNA damage is induced by many factors, some of which naturally occur in the environment. Because of their sessile nature, plants are especially exposed to unfavorable conditions causing DNA damage. In response to this damage, the DDR (DNA damage response) pathway is activated. [...] Read more.
DNA damage is induced by many factors, some of which naturally occur in the environment. Because of their sessile nature, plants are especially exposed to unfavorable conditions causing DNA damage. In response to this damage, the DDR (DNA damage response) pathway is activated. This pathway is highly conserved between eukaryotes; however, there are some plant-specific DDR elements, such as SOG1—a transcription factor that is a central DDR regulator in plants. In general, DDR signaling activates transcriptional and epigenetic regulators that orchestrate the cell cycle arrest and DNA repair mechanisms upon DNA damage. The cell cycle halts to give the cell time to repair damaged DNA before replication. If the repair is successful, the cell cycle is reactivated. However, if the DNA repair mechanisms fail and DNA lesions accumulate, the cell enters the apoptotic pathway. Thereby the proper maintenance of DDR is crucial for plants to survive. It is particularly important for agronomically important species because exposure to environmental stresses causing DNA damage leads to growth inhibition and yield reduction. Thereby, gaining knowledge regarding the DDR pathway in crops may have a huge agronomic impact—it may be useful in breeding new cultivars more tolerant to such stresses. In this review, we characterize different genotoxic agents and their mode of action, describe DDR activation and signaling and summarize DNA repair mechanisms in plants. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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32 pages, 657 KiB  
Review
DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities
by Dana Jurkovicova, Christiana M. Neophytou, Ana Čipak Gašparović and Ana Cristina Gonçalves
Int. J. Mol. Sci. 2022, 23(23), 14672; https://doi.org/10.3390/ijms232314672 - 24 Nov 2022
Cited by 34 | Viewed by 5828
Abstract
Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain [...] Read more.
Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients’ prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed. Full article
(This article belongs to the Special Issue DNA Damage Repair in Cancer: Genetics, Molecular Mechanisms, Diagnostic and Therapeutic Perspectives)
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