Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 60462

Share This Special Issue

Special Issue Editor

Prof. Dr. Razmik Mirzayans

E-Mail Website
Guest Editor

Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
Interests: DNA damage response; p53 signaling; senescence; polyploidy; multinucleation; radioresistance; chemoresistance; Li-Fraumeni syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Our genomes are subject to potentially deleterious alterations resulting from endogenous sources, exogenous sources, and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or to eliminate highly injured cells from the proliferating population. Mutations in genes that encode the key players of the DNA surveillance networks are associated with a wide spectrum of human cancer-prone disorders, as well as human cancers.

Anticancer agents have been extensively studied in the context of triggering programmed cell death (apoptosis). Single-cell observation methods have demonstrated heterogeneity in cancer cells within a given tumor and that apoptosis is not always associated with cancer cell demise. For example, cells exhibiting some features of apoptosis post-treatment can undergo a reversal process (anastasis) and survive. In addition, studies with solid tumors and solid tumor-derived cell lines have demonstrated that exposure to moderate, clinically relevant doses of anticancer agents predominantly triggers cancer cell dormancy (sustained proliferation arrest through, e.g., senescence and/or polyploidy) rather than apoptosis. Dormant cancer cells exhibit an enlarged morphology, remain viable, secrete a myriad of tumor promoting factors, and can give rise to progeny with stem cell-like properties.

The purpose of this Special Issue is to provide a comprehensive update on the growing complexity of cellular responses to DNA-damaging agents. Articles on advances in single-cell detection methodology to study the long-term fate of human cells following anticancer treatment are particularly welcomed.

Potential topics include, but are not limited to:

DNA repair deficiency syndromes
DNA repair pathways
Cell cycle checkpoints
Biological outputs orchestrated by p53 signaling
Cancer cell dormancy and disease relapse post-therapy
Reversible apoptosis (anastasis)
Reversible polyploidy/multinucleation (atavistic model of cancer)
Novel therapeutic strategies targeting dormant cancer cells

Dr. Razmik Mirzayans
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

Human DNA repair-deficiency syndromes
DNA damage response
DNA repair
Cell cycle checkpoints
Radiotherapy
Chemotherapy
p53 signaling
Senescence
Apoptosis
Polyploidy
Multinucleation
Stemness
Anastasis
Atavistic model of cancer
Cancer cell dormancy
Single cell analysis

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

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

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

21 pages, 3714 KiB

Open AccessArticle

Phylostratic Shift of Whole-Genome Duplications in Normal Mammalian Tissues towards Unicellularity Is Driven by Developmental Bivalent Genes and Reveals a Link to Cancer

by Olga V. Anatskaya, Alexander E. Vinogradov, Ninel M. Vainshelbaum, Alessandro Giuliani and Jekaterina Erenpreisa

Int. J. Mol. Sci. 2020, 21(22), 8759; https://doi.org/10.3390/ijms21228759 - 19 Nov 2020

Cited by 29 | Viewed by 3397

Abstract

Tumours were recently revealed to undergo a phylostratic and phenotypic shift to unicellularity. As well, aggressive tumours are characterized by an increased proportion of polyploid cells. In order to investigate a possible shared causation of these two features, we performed a comparative phylostratigraphic analysis of ploidy-related genes, obtained from transcriptomic data for polyploid and diploid human and mouse tissues using pairwise cross-species transcriptome comparison and principal component analysis. Our results indicate that polyploidy shifts the evolutionary age balance of the expressed genes from the late metazoan phylostrata towards the upregulation of unicellular and early metazoan phylostrata. The up-regulation of unicellular metabolic and drug-resistance pathways and the downregulation of pathways related to circadian clock were identified. This evolutionary shift was associated with the enrichment of ploidy with bivalent genes (p < 10⁻¹⁶). The protein interactome of activated bivalent genes revealed the increase of the connectivity of unicellulars and (early) multicellulars, while circadian regulators were depressed. The mutual polyploidy-c-MYC-bivalent genes-associated protein network was organized by gene-hubs engaged in both embryonic development and metastatic cancer including driver (proto)-oncogenes of viral origin. Our data suggest that, in cancer, the atavistic shift goes hand-in-hand with polyploidy and is driven by epigenetic mechanisms impinging on development-related bivalent genes. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Graphical abstract

22 pages, 4335 KiB

Open AccessArticle

Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells

by Agnieszka Bojko, Karolina Staniak, Joanna Czarnecka-Herok, Piotr Sunderland, Magdalena Dudkowska, Małgorzata Alicja Śliwińska, Kristine Salmina and Ewa Sikora

Int. J. Mol. Sci. 2020, 21(17), 6084; https://doi.org/10.3390/ijms21176084 - 24 Aug 2020

Cited by 38 | Viewed by 6220

Abstract

The induction of senescence/polyploidization and their role in cancer recurrence is still a poorly explored issue. We showed that MDA-MB-231 and MCF-7 breast cancer cells underwent reversible senescence/polyploidization upon pulse treatment with doxorubicin (dox). Subsequently, senescent/polyploid cells produced progeny (escapers) that possessed the same amount of DNA as parental cells. In a dox-induced senescence/polyploidization state, the accumulation of autophagy protein markers, such as LC3B II and p62/SQSTM1, was observed. However, the senescent cells were characterized by a very low rate of new autophagosome formation and degradation, estimated by autophagic index. In contrast to senescent cells, escapers had a substantially increased autophagic index and transcription factor EB activation, but a decreased level of an autophagy inhibitor, Rubicon, and autophagic vesicles with non-degraded cargo. These results strongly suggested that autophagy in escapers was improved, especially in MDA-MB-231 cells. The escapers of both cell lines were also susceptible to dox-induced senescence. However, MDA-MB-231 cells which escaped from senescence were characterized by a lower number of γH2AX foci and a different pattern of interleukin synthesis than senescent cells. Thus, our studies showed that breast cancer cells can undergo senescence uncoupled from autophagy status, but autophagic flux resumption may be indispensable in cancer cell escape from senescence/polyploidy. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Graphical abstract

28 pages, 8056 KiB

Open AccessArticle

“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres

by Kristine Salmina, Agnieszka Bojko, Inna Inashkina, Karolina Staniak, Magdalena Dudkowska, Petar Podlesniy, Felikss Rumnieks, Ninel M Vainshelbaum, Dace Pjanova, Ewa Sikora and Jekaterina Erenpreisa

Int. J. Mol. Sci. 2020, 21(8), 2779; https://doi.org/10.3390/ijms21082779 - 16 Apr 2020

Cited by 36 | Viewed by 6173

Abstract

Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Graphical abstract

Review

Jump to: Research

23 pages, 1515 KiB

Open AccessReview

The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability

by Amira Fitieh, Andrew J. Locke, Mobina Motamedi and Ismail Hassan Ismail

Int. J. Mol. Sci. 2021, 22(6), 2976; https://doi.org/10.3390/ijms22062976 - 15 Mar 2021

Cited by 19 | Viewed by 6649

Abstract

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Figure 1

12 pages, 2858 KiB

Open AccessReview

Do TUNEL and Other Apoptosis Assays Detect Cell Death in Preclinical Studies?

by Razmik Mirzayans and David Murray

Int. J. Mol. Sci. 2020, 21(23), 9090; https://doi.org/10.3390/ijms21239090 - 29 Nov 2020

Cited by 131 | Viewed by 11142

Abstract

The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay detects DNA breakage by labeling the free 3ʹ-hydroxyl termini. Given that genomic DNA breaks arise during early and late stages of apoptosis, TUNEL staining continues to be widely used as a measure of apoptotic cell death. The advantages of the assay include its relative ease of performance and the broad availability of TUNEL assay kits for various applications, such as single-cell analysis of apoptosis in cell cultures and tissue samples. However, as briefly discussed herein, aside from some concerns relating to the specificity of the TUNEL assay itself, it was demonstrated some twenty years ago that the early stages of apoptosis, detected by TUNEL, can be reversed. More recently, compelling evidence from different biological systems has revealed that cells can recover from even late stage apoptosis through a process called anastasis. Specifically, such recovery has been observed in cells exhibiting caspase activation, genomic DNA breakage, phosphatidylserine externalization, and formation of apoptotic bodies. Furthermore, there is solid evidence demonstrating that apoptotic cells can promote neighboring tumor cell repopulation (e.g., through caspase-3-mediated secretion of prostaglandin E₂) and confer resistance to anticancer therapy. Accordingly, caution should be exercised in the interpretation of results obtained by the TUNEL and other apoptosis assays (e.g., caspase activation) in terms of apoptotic cell demise. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Figure 1

22 pages, 1695 KiB

Open AccessReview

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

by Quinn Storozynsky and Mary M. Hitt

Int. J. Mol. Sci. 2020, 21(22), 8877; https://doi.org/10.3390/ijms21228877 - 23 Nov 2020

Cited by 124 | Viewed by 8391

Abstract

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Figure 1

29 pages, 1210 KiB

Open AccessReview

XPA: DNA Repair Protein of Significant Clinical Importance

by Lucia Borszéková Pulzová, Thomas A. Ward and Miroslav Chovanec

Int. J. Mol. Sci. 2020, 21(6), 2182; https://doi.org/10.3390/ijms21062182 - 22 Mar 2020

Cited by 45 | Viewed by 6119

Abstract

The nucleotide excision repair (NER) pathway is activated in response to a broad spectrum of DNA lesions, including bulky lesions induced by platinum-based chemotherapeutic agents. Expression levels of NER factors and resistance to chemotherapy has been examined with some suggestion that NER plays a role in tumour resistance; however, there is a great degree of variability in these studies. Nevertheless, recent clinical studies have suggested Xeroderma Pigmentosum group A (XPA) protein, a key regulator of the NER pathway that is essential for the repair of DNA damage induced by platinum-based chemotherapeutics, as a potential prognostic and predictive biomarker for response to treatment. XPA functions in damage verification step in NER, as well as a molecular scaffold to assemble other NER core factors around the DNA damage site, mediated by protein–protein interactions. In this review, we focus on the interacting partners and mechanisms of regulation of the XPA protein. We summarize clinical oncology data related to this DNA repair factor, particularly its relationship with treatment outcome, and examine the potential of XPA as a target for small molecule inhibitors. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Figure 1

14 pages, 890 KiB

Open AccessReview

Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy

by Jessica Dörnen, Mareike Sieler, Julian Weiler, Silvia Keil and Thomas Dittmar

Int. J. Mol. Sci. 2020, 21(5), 1811; https://doi.org/10.3390/ijms21051811 - 6 Mar 2020

Cited by 28 | Viewed by 5813

Abstract

The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Figure 1

20 pages, 1093 KiB

Open AccessReview

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

by Razmik Mirzayans and David Murray

Int. J. Mol. Sci. 2020, 21(4), 1308; https://doi.org/10.3390/ijms21041308 - 15 Feb 2020

Cited by 53 | Viewed by 5101

Abstract

A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century. Full article

(This article belongs to the Special Issue The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond)

► Show Figures

Journal Menu

Journal Browser

The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI