Variability in DNA repair and individual susceptibility to genotoxins

1995 ◽  
Vol 41 (12) ◽  
pp. 1848-1853 ◽  
Author(s):  
S A Kyrtopoulos
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protective Role ◽  
Interindividual Variation ◽  
Human Populations ◽  
Cytostatic Drugs ◽  
Dna Damage And Repair ◽  
Cellular Protection ◽  
Methylated Dna ◽  
Methylating Agents

Abstract DNA repair is an important mechanism of cellular protection from the effects of genotoxic chemicals. Although extensive evidence from studies in experimental systems indicates that variation in DNA repair can significantly influence susceptibility to genotoxins, corresponding studies in human populations are so far limited, mainly because of methodological difficulties. One system, using observations of the accumulation and repair of DNA damage in cancer patients treated with alkylating cytostatic drugs, has provided useful information for assessing the effects of interindividual variation in DNA repair activity on the induction of genotoxic effects in humans. The most detailed studies of this kind have been carried out on patients with cancer (i.e., Hodgkin disease, malignant melanoma) treated with the methylating cytostatic drugs procarbazine or dacarbazine; these studies have provided detailed information on dose-response relationships. They have also demonstrated the protective role of the repair enzyme O6-alkylguanine-DNA alkyltransferase against the accumulation of the premutagenic methylated DNA lesion O6-methylguanine in patients' DNA. Given the strong evidence that exposure of the general population to environmental methylating agents may be extensive, as indicated by the frequent discovery of methylated DNA adducts in human DNA, data on DNA damage and repair in alkylating drug-treated patients and their modulation by host factors may prove useful in efforts to assess the possible carcinogenic risks posed by exposure to environmental methylating agents.

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadezda V. Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Point Mutations ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
C Elegans ◽  
Dna Repair Deficiency ◽  
Dna Alterations ◽  
Repair Pathways

AbstractCells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

scholarly journals A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 453 ◽  
Author(s):  
Sudhir Raghavan ◽  
David S. Baskin ◽  
Martyn A. Sharpe
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Adducts ◽  
Alkylating Agents ◽  
Chemotherapeutic Agents ◽  
Dna Alkylation ◽  
Methylated Dna ◽  
Methylguanine Methyltransferase ◽  
Discrete Populations

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.

scholarly journals DNA Repair Biosensor-Identified DNA Damage Activities of Endophyte Extracts from Garcinia cowa

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1680
Author(s):  
Tassanee Lerksuthirat ◽  
Rakkreat Wikiniyadhanee ◽  
Sermsiri Chitphuk ◽  
Wasana Stitchantrakul ◽  
Somponnat Sampattavanich ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Fluorescent Proteins ◽  
Strand Break ◽  
Control Group ◽  
Focus Formation ◽  
Dna Damage And Repair ◽  
Biological Compounds ◽  
Repair Pathways ◽  
Garcinia Cowa

Recent developments in chemotherapy focus on target-specific mechanisms, which occur only in cancer cells and minimize the effects on normal cells. DNA damage and repair pathways are a promising target in the treatment of cancer. In order to identify novel compounds targeting DNA repair pathways, two key proteins, 53BP1 and RAD54L, were tagged with fluorescent proteins as indicators for two major double strand break (DSB) repair pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). The engineered biosensor cells exhibited the same DNA repair properties as the wild type. The biosensor cells were further used to investigate the DNA repair activities of natural biological compounds. An extract from Phyllosticta sp., the endophyte isolated from the medicinal plant Garcinia cowa Roxb. ex Choisy, was tested. The results showed that the crude extract induced DSB, as demonstrated by the increase in the DNA DSB marker γH2AX. The damaged DNA appeared to be repaired through NHEJ, as the 53BP1 focus formation in the treated fraction was higher than in the control group. In conclusion, DNA repair-based biosensors are useful for the preliminary screening of crude extracts and biological compounds for the identification of potential targeted therapeutic drugs.

scholarly journals Recent Physical Activity in Relation to DNA Damage and Repair Using the Comet Assay

2014 ◽  
Vol 11 (4) ◽  
pp. 770-776 ◽  
Author(s):  
Stephanie Whisnant Cash ◽  
Shirley A.A. Beresford ◽  
Thomas L. Vaughan ◽  
Patrick J. Heagerty ◽  
Leslie Bernstein ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Damage ◽  
Dna Repair ◽  
Comet Assay ◽  
High Intensity ◽  
Total Activity ◽  
Washington State ◽  
Dna Damage And Repair ◽  
Activity Intensity ◽  
Very High

Background:Limited evidence suggests that very high-intensity exercise is positively associated with DNA damage but moderate exercise may be associated with DNA repair.Methods:Participants were 220 healthy, Washington State 50- to 76-year-olds in the validity/biomarker substudy of the VITamins And Lifestyle (VITAL) cohort, who provided blood samples and completed questionnaires assessing recent physical activity and demographic and health factors. Measures included nested activity subsets: total activity, moderate- plus high-intensity activity, and high-intensity activity. DNA damage (n = 122) and repair (n = 99) were measured using the comet assay. Multivariate linear regression was used to estimate regression coefficients and associated 95% confidence intervals (CIs) for relationships between MET-hours per week of activity and each DNA outcome (damage, and 15- and 60-minute repair capacities).Results:DNA damage was not associated with any measure of activity. However, 60-minute DNA repair was positively associated with both total activity (β = 0.21, 95% CI: 0.0057–0.412; P = .044) and high-intensity activity (β = 0.31, 95% CI: 0.20–0.60; P = .036), adjusting for age, sex, BMI, and current multivitamin use.Conclusions:This study is the first to assess broad ranges of activity intensity levels related to DNA damage and repair. Physical activity was unrelated to DNA damage but was associated with increased repair.

DNA Damage and Repair, Volume I: DNA Repair in Prokaryotes and Lower Eukaryotes

1998 ◽  
Vol 149 (6) ◽  
pp. 654
Author(s):  
Robert B. Painter ◽  
Jac A. Nickoloff ◽  
Merl F. Hoekstra
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage And Repair ◽  
Lower Eukaryotes

scholarly journals DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication

2021 ◽  
Vol 14 ◽  
Author(s):  
Haibo Wang ◽  
Manohar Kodavati ◽  
Gavin W. Britz ◽  
Muralidhar L. Hegde
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Genome Instability ◽  
Clinical Manifestations ◽  
Ros Generation ◽  
Dna Damage And Repair ◽  
Repair Deficiency ◽  
Therapeutic Development

Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.

scholarly journals RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer

2020 ◽  
Author(s):  
Damian Wojtowicz ◽  
Jan Hoinka ◽  
Bayarbaatar Amgalan ◽  
Yoo-Ah Kim ◽  
Teresa M. Przytycka
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Therapeutic Implications ◽  
Mutational Landscape ◽  
Repair Processes ◽  
Cancer Genomes ◽  
Current Paradigm ◽  
Mutational Processes

AbstractMany mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RepairSig, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RepairSig was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RepairSig is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RepairSig is publicly available at https://github.com/ncbi/RepairSig.

Expression of critical genes used as prognostic biomarkers and DNA damage in lymphocytes from breast cancer patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10641-10641 ◽  
Author(s):  
F. Franke ◽  
M. Agnoletto ◽  
J. Saffi ◽  
T. Guecheva
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Comet Assay ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
Breast Cancer Patients ◽  
Dna Damage And Repair ◽  
Blood Lymphocytes

10641 Breast cancer is the most common malignancy among women and its rate of mortality is still high. The increase knowledge of breast cancer biology is heaving great impact on determining the clinical prognosis and response to treatment. Impaired DNA repair may elevate the risk of malignant transformation of breast cells due to the accumulation of spontaneous mutations in target genes and increasing susceptibility to exogenous carcinogens. The present study was designed to evaluate the relationship between DNA damage and expression of some critical genes including TP53, c-ERBB2, ER (Estrogen Receptor) and PR (Progesterone Receptor) in breast cancer. Blood samples were obtained from female patients with diagnosed breast cancer before chemotherapy as well as from healthy individuals, and were processed in 24 hours. To evaluate the role of DNA repair in breast cancer we determined the level of DNA damage and the capacity to remove DNA damage induced by hydrogen peroxide in the peripheral blood lymphocytes. For this purpose the alkaline version of the comet assay, which provides a sensitive tool to investigate DNA damage and repair, was applied. The level of basal DNA damage was higher in breast cancer patients compared to the control group. Considerable inter-individual variations of DNA damage and repair in breast cancer patients were observed both before and after the treatment. The correlation between DNA damage in peripheral blood and expression of p53, c-erbB-2, PR and ER was analyzed. This preliminary study indicates that the DNA damage accumulation, observed in peripheral blood lymphocytes of breast cancer patients in early stages, could be attributed to impaired DNA repair. Our results suggest that DNA damage, as evaluated by the comet assay, seems to be useful molecular biomarker for monitoring ongoing exposures to DNA damaging agents. Such a research on the mutagen sensitivity and efficacy of DNA repair could impact on the development of new diagnostic and screening strategies. Work Supported by FAPERGS and GENOTOX (UFRGS). No significant financial relationships to disclose.

Radiosensitization by erlotinib and veliparib in esophageal squamous cell cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 70-70 ◽  
Author(s):  
Alexander Whitley ◽  
Tiffiny Cooper ◽  
Anusha Angajala ◽  
Hoa Trummell ◽  
Josh Jackson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Volume ◽  
Cell Cancer ◽  
Growth Delay ◽  
Esophageal Tumor ◽  
Triple Combination ◽  
Repair Capacity ◽  
Dna Damage And Repair ◽  
Tumor Xenografts

70 Background: Dysregulation of the HER/EGFR family is identified in esophageal cancers and confers resistance and inferior survival rates. In addition to their unique selectivity in killing DNA repair-deficient tumors, poly-ADP ribose polymerase inhibitors (PARPi) can enhance radiation-induced cytotoxicity. We and others have also previously demonstrated attenuation of DNA repair capacity in HER-inhibited cells to induce a contextual synthetic lethal interaction with PARPi. We thus hypothesized that erlotinib, a tyrosine kinase inhibitor directed against HER1/HER2, could induce a transient DNA repair deficit and subsequently increase DNA damage with the PARPi veliparib in esophageal cancer cells while increasing tumor radiation (RT) sensitivity. Methods: Esophageal SCC cell lines (KYSE-30, KYSE-410, and OE-21) were treated with combinations of vehicle, erlotinib, veliparib (a PARP1/2 inhibitor), and RT. DNA damage and repair and signaling proteins were assessed by immunofluorescence staining of cells for DNA damage and repair foci and/or western blot analysis. Cell viability and cytotoxicity were determined via cell proliferation assays and colony formation assays, respectively. Tumor growth delay was assessed in mice bearing esophageal tumor xenografts. Results: Consistent with our hypotheses, erlotinib increased γ-H2AX foci, a marker of DNA double strand breaks (DSBs), in all three esophageal SCC tumor cells. This coincided with reduced DSB-repair capacity as assessed via RAD51 foci and pDNA-PK. Triple combination with erlotinib, veliparib, and RT demonstrated enhanced cytotoxicity. A subsequent increase in Annexin positive cells was observed, indicative of activation of the apoptotic response. Importantly, the triple combination was most effective in suppressing the growth of esophageal tumor xenografts in vivo (2– to 5.5–fold lower tumor volume) relative to other treatment groups. Furthermore, we observed reductions in tumor volume from baseline with this triple combination in 3/6 mice. Conclusions: Thus, the combination of erlotinib, PARPi, and RT can be an innovative and effective treatment strategy to enhance the therapeutic ratio and improve outcomes in esophageal SCC cancer patients.

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