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DNA Damage and DNA Repair Pathways in Cancer Development

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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 (20 November 2024) | Viewed by 10306

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Dr. Kazuhiko Kuwahara

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Department of Diagnostic Pathology, Kindai University Hospital, Osaka 589-8511, Japan
Interests: transcription-coupled DNA damage; lymphomagenesis; mRNA export; breast carcinogenesis; antibody engineering
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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

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Keywords

DNA-damage response
DNA repair molecules
genome instability
cellular senescence
animal models
DNA damage
DNA repair and cancer

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Published Papers (7 papers)

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Research

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23 pages, 20381 KiB

Open AccessArticle

In and out of Replication Stress: PCNA/RPA1-Based Dynamics of Fork Stalling and Restart in the Same Cell

by Teodora Dyankova-Danovska, Sonya Uzunova, Georgi Danovski, Rumen Stamatov, Petar-Bogomil Kanev, Aleksandar Atemin, Aneliya Ivanova, Radoslav Aleksandrov and Stoyno Stoynov

Int. J. Mol. Sci. 2025, 26(2), 667; https://doi.org/10.3390/ijms26020667 - 14 Jan 2025

Viewed by 906

Abstract

Replication forks encounter various impediments, which induce fork stalling and threaten genome stability, yet the precise dynamics of fork stalling and restart at the single-cell level remain elusive. Herein, we devise a live-cell microscopy-based approach to follow hydroxyurea-induced fork stalling and subsequent restart at 30 s resolution. We measure two distinct processes during fork stalling. One is rapid PCNA removal, which reflects the drop in DNA synthesis. The other is gradual RPA1 accumulation up to 2400 nt of ssDNA per fork despite an active intra-S checkpoint. Restoring the nucleotide pool enables a prompt restart without post-replicative ssDNA and a smooth cell cycle progression. ATR, but not ATM inhibition, accelerates hydroxyurea-induced RPA1 accumulation nine-fold, leading to RPA1 exhaustion within 20 min. Fork restart under ATR inhibition led to the persistence of ~600 nt ssDNA per fork after S-phase, which reached 2500 nt under ATR/ATM co-inhibition, with both scenarios leading to mitotic catastrophe. MRE11 inhibition had no effect on PCNA/RPA1 dynamics regardless of ATR activity. E3 ligase RAD18 was recruited at stalled replication forks in parallel to PCNA removal. Our results shed light on fork dynamics during nucleotide depletion and provide a valuable tool for interrogating the effects of replication stress-inducing anti-cancer agents. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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14 pages, 2562 KiB

Open AccessArticle

Oleanolic Acid Modulates DNA Damage Response to Camptothecin Increasing Cancer Cell Death

by Giulio Mazzarotti, Maria Cuomo, Maria Carmen Ragosta, Andrea Russo, Margherita D’Angelo, Annamaria Medugno, Giuseppe Maria Napolitano, Carmelina Antonella Iannuzzi, Iris Maria Forte, Rosa Camerlingo, Sharon Burk, Francesco Errichiello, Luigi Frusciante, Martino Forino, Maria Rosaria Campitiello, Michelino De Laurentiis, Antonio Giordano and Luigi Alfano

Int. J. Mol. Sci. 2024, 25(24), 13475; https://doi.org/10.3390/ijms252413475 - 16 Dec 2024

Cited by 1 | Viewed by 1718

Abstract

Targeting DNA damage response (DDR) pathways represents one of the principal approaches in cancer therapy. However, defects in DDR mechanisms, exhibited by various tumors, can also promote tumor progression and resistance to therapy, negatively impacting patient survival. Therefore, identifying new molecules from natural extracts could provide a powerful source of novel compounds for cancer treatment strategies. In this context, we investigated the role of oleanolic acid (OA), identified in fermented Aglianico red grape pomace, in modulating the DDR in response to camptothecin (CPT), an inhibitor of topoisomerase I. Specifically, we found that OA can influence the choice of DNA repair pathway upon CPT treatment, shifting the repair process from homologous recombination gene conversion to single-strand annealing. Moreover, our data demonstrate that combining sub-lethal concentrations of OA with CPT enhances the efficacy of topoisomerase I inhibition compared to CPT alone. Overall, these findings highlight a new role for OA in the DDR, leading to a more mutagenic DNA repair pathway and increased sensitivity in the HeLa cancer cell line. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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9 pages, 274 KiB

Open AccessCommunication

Germline Variants in DNA Interstrand-Cross Link Repair Genes May Contribute to Increased Susceptibility for Serrated Polyposis Syndrome

by Patrícia Silva, Inês Francisco, Bruno Filipe, Pedro Lage, Isadora Rosa, Sofia Fernandes, Ricardo Fonseca, Paula Rodrigues, Joana Parreira, Isabel Claro and Cristina Albuquerque

Int. J. Mol. Sci. 2024, 25(21), 11848; https://doi.org/10.3390/ijms252111848 - 4 Nov 2024

Viewed by 1256

Abstract

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), is still poorly understood. In a previous study, we proposed the existence of two molecular entities amongst SPS-FHP/CRC families, proximal/whole-colon and distal SPS-FHP/CRC, according to the preferential location of lesions and somatic events involved in tumor initiation. In the present study, we aimed to investigate these distinct subgroups of SPS patients in a larger cohort at the germline level and to identify the genetic defects underlying an inherited susceptibility for these two entities. Next-generation sequencing was performed using multigene analysis with a custom-designed panel in a Miseq platform in 60 SPS patients (with and without/unknown FHP/CRC). We found germline pathogenic variants in 6/60 patients (ATM, FANCM, MITF, RAD50, RAD51C, and RNF43). We also found variants of unknown significance (VUS), with prediction of probable damaging effect in 23/60 patients (ATM, BLM, BRCA1, FAN1, ERCC2, ERCC3, FANCA, FANCD2, FANCL, MSH2, MSH6, NTHL1, PALB2, PDGFRA, PMS2, PTCH1, RAD51C, RAD51D, RECQL4, TSC2, WRN, and XRCC5 genes). Most variants were detected in gene coding for proteins of the Fanconi Anemia (FA) pathway involved in the DNA Interstrand-Cross Link repair (ICLR). Notably, variants in ICLR genes were significantly more frequent in the proximal/whole-colon than in the distal subgroup [15/44 (34%) vs 1/16 (6%), p = 0.025], as opposed to the non-ICLR genes that were slightly more frequent in the distal group [8/44 (18%) vs. 5/16 (31%), p > 0.05]. Germline defects in the DNA-ICLR genes may contribute to increased serrated colorectal polyps/carcinoma risk in SPS patients, particularly in proximal/whole-colon SPS. The inclusion of DNA-ICLR genes in the genetic diagnosis of SPS patients, mainly in those with proximal/whole-colon lesions, should be considered and validated by other studies. In addition, patients with germline defects in the DNA-ICLR genes may be more sensitive to treatment with platinum-based therapeutics, which can have implications in the clinical management of these patients. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

16 pages, 2874 KiB

Open AccessArticle

Age-Dependent Differences in Radiation-Induced DNA Damage Responses in Intestinal Stem Cells

by Guanyu Zhou, Tsutomu Shimura, Taiki Yoneima, Akiko Nagamachi, Akinori Kanai, Kazutaka Doi and Megumi Sasatani

Int. J. Mol. Sci. 2024, 25(18), 10213; https://doi.org/10.3390/ijms251810213 - 23 Sep 2024

Viewed by 1512

Abstract

Age at exposure is a critical modifier of the risk of radiation-induced cancer. However, the effects of age on radiation-induced carcinogenesis remain poorly understood. In this study, we focused on tissue stem cells using Lgr5-eGFP-ires-Cre^ERT2 mice to compare radiation-induced DNA damage responses between Lgr5+ and Lgr5- intestinal stem cells. Three-dimensional immunostaining analyses demonstrated that radiation induced apoptosis and the mitotic index more efficiently in adult Lgr5- stem cells than in adult Lgr5+ stem cells but not in infants, regardless of Lgr5 expression. Supporting this evidence, rapid and transient p53 activation occurred after irradiation in adult intestinal crypts but not in infants. RNA sequencing revealed greater variability in gene expression in adult Lgr5+ stem cells than in infant Lgr5+ stem cells after irradiation. Notably, the cell cycle and DNA repair pathways were more enriched in adult stem cells than in infant stem cells after irradiation. Our findings suggest that radiation-induced DNA damage responses in mouse intestinal crypts differ between infants and adults, potentially contributing to the age-dependent susceptibility to radiation carcinogenesis. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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13 pages, 2261 KiB

Open AccessArticle

Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models

by Steffie Revia, Felix Neumann, Julia Jabs, Florian Orio, Christian Sirrenberg, Astrid Zimmermann, Christiane Amendt and Joachim Albers

Int. J. Mol. Sci. 2024, 25(10), 5120; https://doi.org/10.3390/ijms25105120 - 8 May 2024

Viewed by 1724

Abstract

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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Review

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16 pages, 2858 KiB

Open AccessReview

Tumorigenesis Caused by Aberrant Expression of GANP, a Central Component in the Mammalian TREX-2 Complex—Lessons from Transcription-Coupled DNA Damages

by Andri Rezano, Naomi Gondo, Yasuhiro Sakai, Yuko Nakamura, Suchada Phimsen, Tokio Tani, Akihiko Ito, Seiji Okada and Kazuhiko Kuwahara

Int. J. Mol. Sci. 2024, 25(24), 13612; https://doi.org/10.3390/ijms252413612 - 19 Dec 2024

Viewed by 765

Abstract

DNA is frequently damaged by genotoxic stresses such as ionizing radiation, reactive oxygen species, and nitrogen species. DNA damage is a key contributor to cancer initiation and progression, and thus the precise and timely repair of these harmful lesions is required. Recent studies revealed transcription as a source of genome instability, and transcription-coupled DNA damage has been a focus in cancer research. Impaired mRNA export is closely related to DNA damage through R-loop formation. The molecular machineries of transcription-coupled DNA damage have been extensively analyzed in Saccharomyces cerevisiae. However, the molecular basis of these phenomena in higher eukaryotes remains elusive. In this review, we focus on the relationship between deregulated mRNA export through the transcription-export-2 (TREX-2) complex and cancer development. Particularly, the expression of germinal center-associated nuclear protein (GANP), a molecular scaffold in the TREX-2 complex, is highly associated with tumorigenesis in mice and humans. Although the deregulated expression of other components in the TREX-2 complex might affect cancer development, we have directly demonstrated the significance of GANP in tumorigenesis using genetically modified mice. Additionally, we describe recent evidence for medical applications demonstrating that the downregulation of the other components may be a good candidate for a chemotherapeutic target in terms of reducing the side effects. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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12 pages, 1135 KiB

Open AccessReview

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response

by Harsh Patel, M. Saeed Sheikh and Ying Huang

Int. J. Mol. Sci. 2024, 25(11), 5854; https://doi.org/10.3390/ijms25115854 - 28 May 2024

Viewed by 1507

Abstract

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair Pathways in Cancer Development)

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