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Scientific Reports Apr 2022To combat the various DNA lesions and their harmful effects, cells have evolved different strategies, collectively referred as DNA damage response (DDR). The DDR largely...
To combat the various DNA lesions and their harmful effects, cells have evolved different strategies, collectively referred as DNA damage response (DDR). The DDR largely relies on intranuclear protein networks, which sense DNA lesions, recruit DNA repair enzymes, and coordinates several aspects of the cellular response, including a temporary cell cycle arrest. In addition, external cues mediated by the surface EGF receptor (EGFR) through downstream signaling pathways contribute to the cellular DNA repair capacity. However, cell cycle progression driven by EGFR activation should be reconciled with cell cycle arrest necessary for effective DNA repair. Here, we show that in damaged cells, the expression of Mig-6 (mitogen-inducible gene 6), a known regulator of EGFR signaling, is reduced resulting in heightened EGFR phosphorylation and downstream signaling. These changes in Mig-6 expression and EGFR signaling do not occur in cells deficient of Mre-11, a component of the MRN complex, playing a central role in double-strand break (DSB) repair or when cells are treated with the MRN inhibitor, mirin. RNAseq and functional analysis reveal that DNA damage induces a shift in cell response to EGFR triggering that potentiates DDR-induced p53 pathway and cell cycle arrest. These data demonstrate that the cellular response to EGFR triggering is skewed by components of the DDR, thus providing a plausible explanation for the paradox of the known role played by a growth factor such as EGFR in the DNA damage repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; ErbB Receptors
PubMed: 35388101
DOI: 10.1038/s41598-022-09779-5 -
Acta Biochimica Et Biophysica Sinica May 2022DNA damage repair and innate immunity are two conserved mechanisms that both function in cellular stress responses. Recently, an increasing amount of evidence has... (Review)
Review
DNA damage repair and innate immunity are two conserved mechanisms that both function in cellular stress responses. Recently, an increasing amount of evidence has uncovered the close relationship between these two ancient biological processes. Here, we review the classical function of factors involved in DNA repair, and especially double-strand break repair, in innate immunity; more importantly, we discuss the novel roles of DNA repair factors in regulating innate immunity and . In addition, we also review the roles of DNA repair, innate immunity and their crosstalk in human diseases, which suggest that these two pathways may be compelling targets for disease prevention and treatment.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Nucleic Acids
PubMed: 35975605
DOI: 10.3724/abbs.2022061 -
Mutation Research. Reviews in Mutation... 2021The purpose of this review is to evaluate the literature on the genotoxicity of cumene (CAS # 98-82-8) and to assess the role of mutagenicity, if any, in the mode of... (Review)
Review
The purpose of this review is to evaluate the literature on the genotoxicity of cumene (CAS # 98-82-8) and to assess the role of mutagenicity, if any, in the mode of action for cumene-induced rodent tumors. The studies reviewed included microbial mutagenicity, DNA damage/ repair, cytogenetic effects, and gene mutations. In reviewing these studies, attention was paid to their conformance to applicable OECD test guidelines which are considered as internationally recognized standards for performing these assays. Cumene was not a bacterial mutagen and did not induce Hprt mutations in CHO cell cultures. In the primary rat hepatocyte cultures, cumene induced unscheduled DNA synthesis in one study but this response could not be reproduced in an independent study using a similar protocol. In a study that is not fully compliant to the current OECD guideline, no increase in chromosomal aberrations was observed in CHO cells treated with cumene. The weight of the evidence (WoE) from multiple in vivo studies indicates that cumene is not a clastogen or aneugen. The weak positive response in an in vivo comet assay in the rat liver and mouse lung tissues is of questionable significance due to several study deficiencies. The genotoxicity profile of cumene does not match that of a classic DNA-reactive molecule and the available data does not support a conclusion that cumene is an in vivo mutagen. As such, mutagenicity does not appear to be an early key event in cumene-induced rodent tumors and alternate hypothesized non-mutagenic modes-of-action are presented. Further data are necessary to rule in or rule out a particular MoA.
Topics: Animals; CHO Cells; Comet Assay; Cricetulus; DNA Damage; Humans; Mutagenesis; Mutagenicity Tests; Mutation; Rats
PubMed: 34083043
DOI: 10.1016/j.mrrev.2021.108364 -
Genes Aug 2020DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and... (Review)
Review
DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; Genomic Instability; Humans; Neoplasms; Signal Transduction
PubMed: 32854236
DOI: 10.3390/genes11090990 -
Molecules (Basel, Switzerland) Dec 2020The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic... (Review)
Review
The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic material between homologous chromosomes by the crossover mechanism. This mechanism not only requires correct pairing of homologous chromosomes but also efficient repair of the induced DNA double-strand breaks. Oocytes have evolved a unique quality control system that eliminates cells if chromosomes do not correctly align or if DNA repair is not possible. Central to this monitoring system that is conserved from nematodes and fruit fly to humans is the p53 protein family, and in vertebrates in particular p63. In mammals, oocytes are stored for a long time in the prophase of meiosis I which, in humans, can last more than 50 years. During the entire time of this arrest phase, the DNA damage checkpoint remains active. The treatment of female cancer patients with DNA damaging irradiation or chemotherapeutics activates this checkpoint and results in elimination of the oocyte pool causing premature menopause and infertility. Here, we review the molecular mechanisms of this quality control system and discuss potential therapeutic intervention for the preservation of the oocyte pool during chemotherapy.
Topics: Animals; Cell Death; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Oocytes
PubMed: 33287328
DOI: 10.3390/molecules25235714 -
Molecules (Basel, Switzerland) Feb 2022Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality... (Review)
Review
Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.
Topics: Chromatin; Cluster Analysis; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Radiation, Ionizing
PubMed: 35268641
DOI: 10.3390/molecules27051540 -
Archives of Endocrinology and Metabolism 2019Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ... (Review)
Review
Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ composed of multiple cell types. Interactions between malignant and non-transformed cells and tissues create a tumor microenvironment (TME) comprising epithelial cancer cells, cancer stem cells, non-tumorous cells, stromal cells, immune-inflammatory cells, blood and lymphatic vascular network, and extracellular matrix. We review reports and present a hypothesis that postulates the involvement of growth hormone (GH) in field cancerization. We discuss GH contribution to TME, promoting epithelial-to-mesenchymal transition, accumulation of unrepaired DNA damage, tumor vascularity, and resistance to therapy. Arch Endocrinol Metab. 2019;63(6):568-75.
Topics: DNA Damage; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Human Growth Hormone; Humans; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 31939481
DOI: 10.20945/2359-3997000000186 -
Molecular Cell Apr 2024Micronuclei (MN) are induced by various genotoxic stressors and amass nuclear- and cytoplasmic-resident proteins, priming the cell for MN-driven signaling cascades....
Micronuclei (MN) are induced by various genotoxic stressors and amass nuclear- and cytoplasmic-resident proteins, priming the cell for MN-driven signaling cascades. Here, we measured the proteome of micronuclear, cytoplasmic, and nuclear fractions from human cells exposed to a panel of six genotoxins, comprehensively profiling their MN protein landscape. We find that MN assemble a proteome distinct from both surrounding cytoplasm and parental nuclei, depleted of spliceosome and DNA damage repair components while enriched for a subset of the replisome. We show that the depletion of splicing machinery within transcriptionally active MN contributes to intra-MN DNA damage, a known precursor to chromothripsis. The presence of transcription machinery in MN is stress-dependent, causing a contextual induction of MN DNA damage through spliceosome deficiency. This dataset represents a unique resource detailing the global proteome of MN, guiding mechanistic studies of MN generation and MN-associated outcomes of genotoxic stress.
Topics: Humans; Proteome; Proteomics; Cell Nucleus; DNA Damage; Chromothripsis
PubMed: 38423013
DOI: 10.1016/j.molcel.2024.02.001 -
Strahlentherapie Und Onkologie : Organ... Dec 2023This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune... (Review)
Review
PURPOSE
This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors.
METHODS
A literature search was conducted in PubMed using the terms ("DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*") until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed.
RESULTS
Modern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here.
CONCLUSION
The combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.
Topics: Humans; Neoplasms; DNA Repair; DNA Damage
PubMed: 37420037
DOI: 10.1007/s00066-023-02103-8 -
Molecular Biology Reports Dec 2022Damage-specific DNA-binding protein 2 (DDB2) was initially identified as a component of the damage-specific DNA-binding heterodimeric complex, which cooperates with... (Review)
Review
Damage-specific DNA-binding protein 2 (DDB2) was initially identified as a component of the damage-specific DNA-binding heterodimeric complex, which cooperates with other proteins to repair UV-induced DNA damage. DDB2 is involved in the occurrence and development of cancer by affecting nucleotide excision repair (NER), cell apoptosis, and premature senescence. DDB2 also affects the sensitivity of cancer cells to radiotherapy and chemotherapy. In addition, a recent study found that DDB2 is a pathogenic gene for hepatitis and encephalitis. In recent years, there have been few relevant literature reports on DDB2, so there is still room for further research about it. In this paper, the molecular mechanisms of different biological processes involving DDB2 are reviewed in detail to provide theoretical support for research on drugs that can target DDB2.
Topics: Ultraviolet Rays; DNA Repair; DNA-Binding Proteins; DNA Damage; Apoptosis
PubMed: 36190612
DOI: 10.1007/s11033-022-07963-4