scholarly journals Structure-driven effects on genomic DNA damage propensity at G-quadruplex sites

2021 ◽  
Author(s):  
Adib A Abdullah ◽  
Claudia Feng ◽  
Patrick Pflughaupt ◽  
Aleksandr B. Sahakyan
Keyword(s):  
Dna Damage ◽  
Pyrimidine Dimer ◽  
Exogenous Dna ◽  
G Quadruplex ◽  
Radiation Induced ◽  
Opposite Strand ◽  
Natural Decay ◽  
Ultrasound Sonication ◽  
Damage Type ◽  
Simple Combination

Our genome contains about half a million sites capable of forming G-quadruplex (G4) structures. Such structural formations, often localised at important regulatory loci, have high capability of altering the predisposition of corresponding genomic spans to endogenous and exogenous DNA damage. In this work, we devised an approach to systematically enrich and zoom onto structure-driven effects on the propensity to undergo 9 types of DNA damage: ultraviolet radiation-induced pyrimidine-pyrimidone (6-4) photoproduct PP and cyclobutane pyrimidine dimer CPD couplings (two dyad-based subtypes in each), cisplatin-mediated G-G crosslinks, reactive oxygen species induced 8-oxoguanine damage, DNA fragmentation upon natural decay and fossilisation, breakages from artificial enzymatic cleavage and ultrasound sonication. Our results indicate that the structural effects on DNA damageability at G4 sites are not a simple combination of shielding (G4 strand) and de-shielding (opposite strand) against damaging factors, and the outcomes have different patterns and variation from one damage type to another, highly dependent on the G4 strength and relative strand localisation. The results are accompanied by electronic structure calculations, detailed structural parallels and considerations.

scholarly journals A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiraporn Kantapan ◽  
Siwaphon Paksee ◽  
Aphidet Duangya ◽  
Padchanee Sangthong ◽  
Sittiruk Roytrakul ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Mammosphere Formation ◽  
Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

scholarly journals Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

2020 ◽  
Vol 63 (6) ◽  
pp. 3090-3103 ◽  
Author(s):  
Jussara Amato ◽  
Giulia Miglietta ◽  
Rita Morigi ◽  
Nunzia Iaccarino ◽  
Alessandra Locatelli ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Genome Instability ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
G Quadruplex ◽  
Selective Ligands

scholarly journals Inhibition of γ-Radiation Induced DNA Damage in Plasmid pBR322 by TMG, a Water-soluble Derivative of Vitamin E

2002 ◽  
Vol 43 (2) ◽  
pp. 153-153 ◽  
Author(s):  
REMA RAJAGOPALAN ◽  
KHALIDA WANI ◽  
NAGARAJ G. HUILGOL ◽  
TSUTOMU V. KAGIYA ◽  
CHERUPALLY K. KRISHNAN NAIR
Keyword(s):  
Dna Damage ◽  
Vitamin E ◽  
Water Soluble ◽  
Plasmid Pbr322 ◽  
Γ Radiation ◽  
Radiation Induced

scholarly journals Krüppel-like factor 4 exhibits antiapoptotic activity following γ-radiation-induced DNA damage

Oncogene ◽  
2006 ◽  
Vol 26 (16) ◽  
pp. 2365-2373 ◽  
Author(s):  
A M Ghaleb ◽  
J P Katz ◽  
K H Kaestner ◽  
J X Du ◽  
V W Yang
Keyword(s):  
Dna Damage ◽  
Γ Radiation ◽  
Radiation Induced ◽  
Antiapoptotic Activity

scholarly journals Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3843
Author(s):  
Jeffrey R. Whiteaker ◽  
Tao Wang ◽  
Lei Zhao ◽  
Regine M. Schoenherr ◽  
Jacob J. Kennedy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Limit Of Quantification ◽  
Peripheral Blood Mononuclear ◽  
Atm Kinase ◽  
Support Mechanism ◽  
Radiation Induced ◽  
Pharmacodynamic Biomarkers ◽  
Preclinical And Clinical Studies

The ATM serine/threonine kinase (HGNC: ATM) is involved in initiation of repair of DNA double-stranded breaks, and ATM inhibitors are currently being tested as anti-cancer agents in clinical trials, where pharmacodynamic (PD) assays are crucial to help guide dose and scheduling and support mechanism of action studies. To identify and quantify PD biomarkers of ATM inhibition, we developed and analytically validated a 51-plex assay (DDR-2) quantifying protein expression and DNA damage-responsive phosphorylation. The median lower limit of quantification was 1.28 fmol, the linear range was over 3 orders of magnitude, the median inter-assay variability was 11% CV, and 86% of peptides were stable for storage prior to analysis. Use of the assay was demonstrated to quantify signaling following ionizing radiation-induced DNA damage in both immortalized lymphoblast cell lines and primary human peripheral blood mononuclear cells, identifying PD biomarkers for ATM inhibition to support preclinical and clinical studies.

scholarly journals Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Stephen J. McMahon ◽  
Jan Schuemann ◽  
Harald Paganetti ◽  
Kevin M. Prise
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mechanistic Modelling ◽  
Cellular Survival ◽  
Radiation Induced
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