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Cells
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DNA Damage Response Regulation and Cancer
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DNA Damage Response Regulation and Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Proliferation and Division".

Deadline for manuscript submissions: closed (10 September 2022) | Viewed by 25963

Special Issue Editor

Dr. Michal Goldberg

E-Mail Website
Guest Editor
Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University, 9190401 Jerusalem, Israel
Interests: DNA damage response; DNA double-strand break repair; ubiquitination; UFMylation; DNA damage checkpoint

Special Issue Information

Dear Colleagues,

Genomic instability is an increased tendency of the genome to acquire mutations and changes in chromosomes’ structure and number. It is one of the hallmarks of cancer cells, playing key roles in both cancer initiation and progression. The integrity of the genome is under constant threat from faults in cell cycle regulation and DNA damage induced by endogenous and exogenous sources. The presence of DNA damage in cells activates the DNA damage response (DDR), which senses and responds to the damage via extensive signaling networks. The DDR includes mechanisms that sense and identify the DNA lesion, multiple DNA repair pathways, cell cycle checkpoint activation as well as apoptosis and cellular senescence. DDR factors are commonly regulated by numerous post-translational modifications (PTMs), such as phosphorylation and ubiquitination. This tight regulation of DDR factors by PTMs serves as a barcode for fine-tuning the DDR. 

Mutations in DDR genes are common to cancer cells, and germline mutations in these genes result in genomic instability syndromes, which are characterized by cancer predisposition. Consequently, the DDR is impaired in many cancers, resulting in increased mutagenesis and genomic instability that trigger tumorigenesis. These cancer cells rely more on the existing functional DDR signaling networks, and therefore they are sensitive to the inhibition of those networks. Indeed, inhibitors of numerous DDR pathways are currently used as cancer therapeutic agents, or are currently under clinical trials. 

The focus of this Special Issue is on the DDR. Specifically, we will address the regulation of the DDR, the relationship between the DDR and cancer and DDR-related therapeutic treatments. 

Dr. Michal Goldberg
Guest Editor

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Keywords

  • DNA damage response (DDR)
  • DNA repair
  • post-translational modifications and the DDR
  • DDR-based cancer therapy

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Published Papers (8 papers)

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Research

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11 pages, 1839 KiB  
Article
Interactions of PARP1 Inhibitors with PARP1-Nucleosome Complexes
by Natalya Maluchenko, Darya Koshkina, Anna Korovina, Vasily Studitsky and Alexey Feofanov
Cells 2022, 11(21), 3343; https://doi.org/10.3390/cells11213343 - 23 Oct 2022
Cited by 2 | Viewed by 2076
Abstract
Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions [...] Read more.
Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions of PARP1-nucleosome complexes with PARPi, olaparib (Ola), talazoparib (Tala), and veliparib (Veli) were studied. PARPi trap PARP1 on nucleosomes without affecting the structure of PARP1-nucleosome complexes. The efficiency of PARP1 trapping on nucleosomes increases in the order of Tala>Ola>>Veli, recapitulating the relative trapping efficiencies of PARPi in cells, but different from the relative potency of PARPi to inhibit the catalytic activity of PARP1. The efficiency of PARP1 trapping on nucleosomes correlates with the level of inhibition of auto-PARylation, which otherwise promotes the dissociation of PARP1-nucleosome complexes. The trapping efficiencies of Tala and Ola (but not Veli) are additionally modulated by the enhanced PARP1 binding to nucleosomes. The dissociation of PARP1-nucleosome complexes occurs without a loss of histones and leads to the restoration of the intact structure of nucleosomal DNA. The data suggest that the chromatin structure can considerably affect the efficiency of the PARPi action. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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16 pages, 5345 KiB  
Article
Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor
by Yuta Kobayashi, Matias A. Bustos, Yoshiaki Shoji, Ron D. Jachimowicz, Yosef Shiloh and Dave S. B. Hoon
Cells 2022, 11(20), 3311; https://doi.org/10.3390/cells11203311 - 21 Oct 2022
Cited by 1 | Viewed by 2488
Abstract
Ubiquilin-4 (UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, [...] Read more.
Ubiquilin-4 (UBQLN4) is a proteasomal shuttle factor that directly binds to ubiquitylated proteins and delivers its cargo to the 26S proteasome for degradation. We previously showed that upregulated UBQLN4 determines the DNA damage response (DDR) through the degradation of MRE11A. However, the regulatory mechanism at DNA level, transcriptionally and post-transcriptional levels that control UBQLN4 mRNA levels remains unknown. In this study, we screened 32 solid tumor types and validated our findings by immunohistochemistry analysis. UBQLN4 is upregulated at both mRNA and protein levels and the most significant values were observed in liver, breast, ovarian, lung, and esophageal cancers. Patients with high UBQLN4 mRNA levels had significantly poor prognoses in 20 of 32 cancer types. DNA amplification was identified as the main mechanism promoting UBQLN4 upregulation in multiple cancers, even in the early phases of tumor development. Using CRISPR screen datasets, UBQLN4 was identified as a common essential gene for tumor cell viability in 81.1% (860/1,060) of the solid tumor derived cell lines. Ovarian cancer cell lines with high UBQLN4 mRNA levels were platinum-based chemotherapy resistant, while they were more sensitive to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Our findings highlight the utilities of UBQLN4 as a significant pan-cancer theranostic factor and a precision oncology biomarker for DDR-related drug resistance. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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12 pages, 1993 KiB  
Article
USP29 Deubiquitinates SETD8 and Regulates DNA Damage-Induced H4K20 Monomethylation and 53BP1 Focus Formation
by Yeray Hernández-Reyes, María Cristina Paz-Cabrera, Raimundo Freire and Veronique A. J. Smits
Cells 2022, 11(16), 2492; https://doi.org/10.3390/cells11162492 - 11 Aug 2022
Cited by 2 | Viewed by 2550
Abstract
SETD8 is a histone methyltransferase that plays pivotal roles in several cellular functions, including transcriptional regulation, cell cycle progression, and genome maintenance. SETD8 regulates the recruitment of 53BP1 to sites of DNA damage by controlling histone H4K20 methylation. Moreover, SETD8 levels are tightly [...] Read more.
SETD8 is a histone methyltransferase that plays pivotal roles in several cellular functions, including transcriptional regulation, cell cycle progression, and genome maintenance. SETD8 regulates the recruitment of 53BP1 to sites of DNA damage by controlling histone H4K20 methylation. Moreover, SETD8 levels are tightly regulated in a cell cycle-dependent manner by ubiquitin-dependent proteasomal degradation. Here, we identified ubiquitin-specific peptidase 29, USP29, as a novel regulator of SETD8. Depletion of USP29 leads to decreased SETD8 protein levels, an effect that is independent of the cell cycle. We demonstrate that SETD8 binds to USP29 in vivo, and this interaction is dependent on the catalytic activity of USP29. Wildtype USP29 can deubiquitinate SETD8 in vivo, indicating that USP29 directly regulates SETD8 protein levels. Importantly, USP29 knockdown inhibits the irradiation-induced increase in H4K20 monomethylation, thereby preventing focus formation of 53BP1 in response to DNA damage. Lastly, depletion of USP29 increases the cellular sensitivity to irradiation. These results demonstrate that USP29 is critical for the DNA damage response and cell survival, likely by controlling protein levels of SETD8. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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13 pages, 1315 KiB  
Article
The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response
by Alice Bradbury, Frank T. Zenke, Nicola J. Curtin and Yvette Drew
Cells 2022, 11(15), 2361; https://doi.org/10.3390/cells11152361 - 1 Aug 2022
Cited by 7 | Viewed by 2868
Abstract
Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under [...] Read more.
Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under clinical investigation as monotherapy and in combination with other anticancer agents. Molecular determinants of sensitivity to ATRi are common in ovarian cancer, suggesting the therapeutic potential of ATRi. We investigated the cytotoxicity of the ATRi, VE-821, in a panel of human ovarian cancer cell lines. High grade serous (HGS) cell lines were significantly more sensitive to VE-821 than non-HGS (p ≤ 0.0001) but previously identified determinants of sensitivity (TP53, ATM and BRCA1) were not predictive. Only low RAD51 (p = 0.041), TopBP1 (p = 0.026) and APOBEC3B (p = 0.015) protein expression were associated with increased VE-821 sensitivity. HGS cells had increased levels of RS (pRPASer4/8 and γH2AX nuclear immunofluorescence), and elevated RS predicted sensitivity to VE-821 independently of the cell line subtype. These data suggest that functional assessment of RS biomarkers may be a better predictive biomarker of ATRi response than any single aberrant gene in ovarian cancer and potentially other cancers. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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15 pages, 18589 KiB  
Article
Low-Dose-Rate Irradiation Suppresses the Expression of Cell Cycle-Related Genes, Resulting in Modification of Sensitivity to Anti-Cancer Drugs
by Kiichi Shimabukuro, Takahiro Fukazawa, Akinori Kanai, Hidehiko Kawai, Kengo Mekata, Nobuyuki Hirohashi, Naoya Kakimoto and Keiji Tanimoto
Cells 2022, 11(3), 501; https://doi.org/10.3390/cells11030501 - 31 Jan 2022
Cited by 2 | Viewed by 3281
Abstract
The biological effects of low-dose-rate (LDR) radiation exposure in nuclear power plant accidents and medical uses of ionizing radiation (IR), although being a social concern, remain unclear. In this study, we evaluated the effects of LDR-IR on global gene expression in human cells [...] Read more.
The biological effects of low-dose-rate (LDR) radiation exposure in nuclear power plant accidents and medical uses of ionizing radiation (IR), although being a social concern, remain unclear. In this study, we evaluated the effects of LDR-IR on global gene expression in human cells and aimed to clarify the mechanisms. RNA-seq analyses demonstrated that relatively low dose rates of IR modify gene expression levels in TIG-3 cells under normoxic conditions, but those effects were attenuated under hypoxia-mimicking conditions. Gene set enrichment analysis demonstrated that LDR-IR significantly decreased gene expression related to cell division, cell cycle, mitosis, and the Aurora kinase B and FOXM1 pathways. Quantitative RT-PCR confirmed the down-regulation of AURKB and FOXM1 genes in TIG-3 cells with LDR-IR or hypoxia-mimicking treatments without any dose-rate effect. Knock-down experiments suggested that HIF-1α and HIF-2α, as well as DEC1, participated in down-regulation of AURKB and FOXM1 under DFOM treatments, but to a lesser extent under LDR-IR treatment. FACS and microscopic analyses demonstrated that LDR-IR induced G0/G1 arrest and increased micronucleus or chromosome condensation. Finally, MTT assays demonstrated that LDR-IR decreased sensitivity to paclitaxel or barasertib in TIG-3 cells but not in A549 cells. In conclusion, LDR-IR modifies global gene expression and cell cycle control, resulting in a reduction of sensitivity to anti-cancer chemotherapy in non-cancer cells and thus a reduction in untoward effects (GA). Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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Review

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13 pages, 1497 KiB  
Review
The Interplay between the Cellular Response to DNA Double-Strand Breaks and Estrogen
by Lia Yedidia-Aryeh and Michal Goldberg
Cells 2022, 11(19), 3097; https://doi.org/10.3390/cells11193097 - 1 Oct 2022
Cited by 1 | Viewed by 2260
Abstract
Cancer development is often connected to impaired DNA repair and DNA damage signaling pathways. The presence of DNA damage in cells activates DNA damage response, which is a complex cellular signaling network that includes DNA repair, activation of the cell cycle checkpoints, cellular [...] Read more.
Cancer development is often connected to impaired DNA repair and DNA damage signaling pathways. The presence of DNA damage in cells activates DNA damage response, which is a complex cellular signaling network that includes DNA repair, activation of the cell cycle checkpoints, cellular senescence, and apoptosis. DNA double-strand breaks (DSBs) are toxic lesions that are mainly repaired by the non-homologous end joining and homologous recombination repair (HRR) pathways. Estrogen-dependent cancers, like breast and ovarian cancers, are frequently associated with mutations in genes that play a role in HRR. The female sex hormone estrogen binds and activates the estrogen receptors (ERs), ERα, ERβ and G-protein-coupled ER 1 (GPER1). ERα drives proliferation, while ERβ inhibits cell growth. Estrogen regulates the transcription, stability and activity of numerus DDR factors and DDR factors in turn modulate ERα expression, stability and transcriptional activity. Additionally, estrogen stimulates DSB formation in cells as part of its metabolism and proliferative effect. In this review, we will present an overview on the crosstalk between estrogen and the cellular response to DSBs. We will discuss how estrogen regulates DSB signaling and repair, and how DDR factors modulate the expression, stability and activity of estrogen. We will also discuss how the regulation of HRR genes by estrogen promotes the development of estrogen-dependent cancers. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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25 pages, 1701 KiB  
Review
Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer
by Joan Manils, Laura Marruecos and Concepció Soler
Cells 2022, 11(14), 2157; https://doi.org/10.3390/cells11142157 - 9 Jul 2022
Cited by 5 | Viewed by 4855
Abstract
Although DNA degradation might seem an unwanted event, it is essential in many cellular processes that are key to maintaining genomic stability and cell and organism homeostasis. The capacity to cut out nucleotides one at a time from the end of a DNA [...] Read more.
Although DNA degradation might seem an unwanted event, it is essential in many cellular processes that are key to maintaining genomic stability and cell and organism homeostasis. The capacity to cut out nucleotides one at a time from the end of a DNA chain is present in enzymes called exonucleases. Exonuclease activity might come from enzymes with multiple other functions or specialized enzymes only dedicated to this function. Exonucleases are involved in central pathways of cell biology such as DNA replication, repair, and death, as well as tuning the immune response. Of note, malfunctioning of these enzymes is associated with immune disorders and cancer. In this review, we will dissect the impact of DNA degradation on the DNA damage response and its links with inflammation and cancer. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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18 pages, 1433 KiB  
Review
Telomere Maintenance and the cGAS-STING Pathway in Cancer
by Hiroshi Ebata, Tze Mun Loo and Akiko Takahashi
Cells 2022, 11(12), 1958; https://doi.org/10.3390/cells11121958 - 17 Jun 2022
Cited by 9 | Viewed by 4451
Abstract
Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate [...] Read more.
Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed. Full article
(This article belongs to the Special Issue DNA Damage Response Regulation and Cancer)
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