Radiation-induced chromatid breaks and deficient DNA repair in cancer predisposition

2001 ◽  
Vol 37 (2) ◽  
pp. 87-96 ◽  
Author(s):  
Ram Parshad ◽  
Katherine K. Sanford
Keyword(s):  
Dna Repair ◽  
Cancer Predisposition ◽  
Radiation Induced

983: Bladder Cancer Predisposition: A Pathway-Based Approach to DNA Repair and Cell Cycle Control Genes

2006 ◽  
Vol 175 (4S) ◽  
pp. 317-317
Author(s):  
Xifeng Wu ◽  
Jian Gu ◽  
H. Barton Grossman ◽  
Christopher I. Amos ◽  
Carol Etzel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Dna Repair ◽  
Cell Cycle Control ◽  
Cancer Predisposition

scholarly journals Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 924
Author(s):  
Laurence Blanchard ◽  
Arjan de Groot
Keyword(s):  
Dna Repair ◽  
Deinococcus Radiodurans ◽  
Dna Repair Genes ◽  
Lesion Bypass ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Mutagenesis ◽  
High Doses ◽  
Translesion Polymerases ◽  
Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

Communication of Radiation-Induced Signals in Vivo between DNA Repair Deficient and Proficient Medaka (Oryzias latipes)

2009 ◽  
Vol 43 (9) ◽  
pp. 3335-3342 ◽  
Author(s):  
C. Mothersill ◽  
R. W. Smith ◽  
T. G. Hinton ◽  
K. Aizawa ◽  
C. B. Seymour
Keyword(s):  
Dna Repair ◽  
Oryzias Latipes ◽  
Radiation Induced

UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice

DNA Repair ◽  
2002 ◽  
Vol 1 (2) ◽  
pp. 143-157 ◽  
Author(s):  
Gijsbertus T.J van der Horst ◽  
Lisiane Meira ◽  
Theo G.M.F Gorgels ◽  
Jan de Wit ◽  
Susana Velasco-Miguel ◽  
...  
Keyword(s):  
Cockayne Syndrome ◽  
Cancer Predisposition ◽  
Mutant Mice ◽  
Uvb Radiation ◽  
Radiation Induced Cancer ◽  
Group A ◽  
Radiation Induced

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

KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells

1997 ◽  
Vol 272 (6) ◽  
pp. L1174-L1180 ◽  
Author(s):  
M. Takeoka ◽  
W. F. Ward ◽  
H. Pollack ◽  
D. W. Kamp ◽  
R. J. Panos
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Alveolar Epithelial ◽  
Radiation Induced ◽  
Dna Strand

Administration of exogenous keratinocyte growth factor (KGF) prevents or attenuates several forms of oxidant-mediated lung injury. Because DNA damage in epithelial cells is a component of radiation pneumotoxicity, we determined whether KGF ameliorated DNA strand breaks in irradiated A549 cells. Cells were exposed to 137Cs gamma rays, and DNA damage was measured by alkaline unwinding and ethidium bromide fluorescence after a 30-min recovery period. Radiation induced a dose-dependent increase in DNA strand breaks. The percentage of double-stranded DNA after exposure to 30 Gy increased from 44.6 +/- 3.5% in untreated control cells to 61.6 +/- 5.0% in cells cultured with 100 ng/ml KGF for 24 h (P < 0.05). No reduction in DNA damage occurred when the cells were cultured with KGF but maintained at 0 degree C during and after irradiation. The sparing effect of KGF on radiation-induced DNA damage was blocked by aphidicolin, an inhibitor of DNA polymerases-alpha, -delta, and -epsilon and by butylphenyl dGTP, which blocks DNA polymerase-alpha strongly and polymerases-delta and -epsilon less effectively. However, dideoxythymidine triphosphate, a specific inhibitor of DNA polymerase-beta, did not abrogate the KGF effect. Thus KGF increases DNA repair capacity in irradiated pulmonary epithelial cells, an effect mediated at least in part by DNA polymerases-alpha, -delta, and -epsilon. Enhancement of DNA repair capability after cell damage may be one mechanism by which KGF is able to ameliorate oxidant-mediated alveolar epithelial injury.

scholarly journals Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Ankita Gupta ◽  
Don Mathew ◽  
Shabir Ahmad Bhat ◽  
Sushmita Ghoshal ◽  
Arnab Pal
Keyword(s):  
Dna Repair ◽  
Genetic Variants ◽  
Oropharyngeal Carcinoma ◽  
Dna Repair Genes ◽  
Nucleotide Polymorphisms ◽  
Radical Radiotherapy ◽  
Single Nucleotide ◽  
Radiation Induced ◽  
Repair Genes ◽  
Severe Fibrosis

PurposeTo investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy.Materials and MethodsPatients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient’s follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis.Results179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C&gt;T, rs861539) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G&gt;A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G&gt;T, rs828907) (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G&gt;A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G&gt;T, rs828907) (p=0.010*, OR 26.340, 95% CI 4.014-76.568).ConclusionWe demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

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