A5091310822- DNA Repair Mechanisms
- Carcinogens and Genotoxicity Assessment
- Radioactivity and Radon Measurements
- Genomics and Chromatin Dynamics
- Radiation Therapy and Dosimetry
- Radiation Dose and Imaging
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Genetic factors in colorectal cancer
- Effects of Radiation Exposure
- DNA and Nucleic Acid Chemistry
- Radioactive contamination and transfer
- CRISPR and Genetic Engineering
- Cancer therapeutics and mechanisms
- Mitochondrial Function and Pathology
- Telomeres, Telomerase, and Senescence
- Cancer Genomics and Diagnostics
- Genetics and Neurodevelopmental Disorders
- Glioma Diagnosis and Treatment
- Knowledge Management and Technology
- Cytomegalovirus and herpesvirus research
- Polyomavirus and related diseases
- Plant Genetic and Mutation Studies
University of Calgary
2016-2025
Dalhousie University
2018-2019
Canadian Cancer Society
2019
Cancer Institute (WIA)
2017
Google (United States)
2017
O'Brien Institute
2017
Public Health Department
2017
Technical University of Darmstadt
2013
University of Sussex
2006-2012
DNA double-strand breaks (DSBs) represent an important radiation-induced lesion and impaired DSB repair provides the best available correlation with radiosensitivity. Physical techniques for monitoring require high, non-physiological doses cannot reliably detect subtle defects. One outcome from extensive research into damage response is observation that H2AX, a variant form of histone H2A, undergoes phosphorylation at DSB, creating gammaH2AX foci can be visualized by immunofluorescence....
The p53 tumor suppressor protein preserves genome integrity by regulating growth arrest and apoptosis in response to DNA damage. In ionizing radiation (IR), ATM, the gene product mutated ataxia telangiectasia, stabilizes activates through phosphorylation of Ser15 (indirectly) Ser20. Here we show that on Ser46, a residue important for apoptotic activity, as well Ser9, IR also is dependent ATM kinase. IR-induced at Ser46 was inhibited wortmannin, phosphatidylinositol 3-kinase inhibitor, but...
The DNA-dependent protein kinase (DNA-PK) is required for the repair of DNA double-strand breaks (DSBs), such as those caused by ionizing radiation and other DNA-damaging agents. DNA-PK composed a large catalytic subunit (DNA-PKcs) heterodimer Ku70 Ku80 that assemble on ends double-stranded to form an active serine/threonine complex. Despite in vitro vivo evidence support essential role activity DSBs, physiological targets have remained elusive. We previously shown undergoes...
DNA NHEJ (non-homologous end-joining) is the major DSB (double-strand break) repair pathway in mammalian cells. Although NHEJ-defective cell lines show marked DSB-repair defects, cells defective ATM (ataxia telangiectasia mutated) most DSBs normally. Thus functions independently of signalling. However, ∼15% radiation-induced are repaired with slow kinetics and require nuclease Artemis. persisting presence an inhibitor, ATMi, localize to heterochromatin, suggesting that required for repairing...
Ataxia telangiectasia (ATM) mutated and Artemis, the proteins defective in ataxia a class of Radiosensitive-Severe Combined Immunodeficiency (RS-SCID), respectively, function repair DNA double strand breaks (DSBs), which arise heterochromatic (HC-DSBs) following exposure to ionizing radiation (IR). Here, we examine whether they have protective roles against oxidative damage induced and/or endogenously DSBs. We show that DSBs generated acute G0/G1 cells damaging agent, tert-butyl...
Abstract Human-made buildings can artificially concentrate radioactive radon gas of geologic origin, exposing occupants to harmful alpha particle radiation emissions that damage DNA and increase lung cancer risk. We examined how North American residential exposure varies by modern environmental design, occupant behaviour season. 11,727 were radon-tested using multiple approaches coupled geologic, geographic, architectural, seasonal behavioural data with quality controls. Regional residences...
XLF-Cernunnos (XLF) is a component of the DNA ligase IV–XRCC4 (LX) complex, which functions during non-homologous end joining (NHEJ). Here, we use biochemical and cellular approaches to probe impact XLF on LX activities. We show that stimulates adenylation complexes de-adenylated by pyrophosphate or following decharging ligation. enhances ligation activity in an ATP-independent dependent manner. stimulation can be attributed enhanced end-bridging. Whilst ATP alone fails stimulate activity,...
ATM-dependent initiation of the radiation-induced G(2)/M checkpoint arrest is well established. Recent results have shown that majority DNA double-strand breaks (DSBs) in G(2) phase are repaired by nonhomologous end joining (NHEJ), while approximately 15% DSBs slowly homologous recombination. Here, we evaluate how maintained irradiated cells, light our current understanding DSB repair. We show resection at a subset leads to ATR-dependent Chk1 activation. ATR-Seckel syndrome which fail...
Although DNA non-homologous end-joining repairs most double-strand breaks (DSBs) in G2 phase, late repairing DSBs undergo resection and repair by homologous recombination (HR). Based on parallels to the situation G1 cells, previous work has suggested that HR predominantly localize regions of heterochromatin (HC). By using H3K9me3 H4K20me3 identify HC regions, we substantiate extend evidence, suggesting HC-DSBs HR. Next, examine roles for 53BP1 BRCA1 this process. Previous studies have shown...
Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes double-strand break (DSB) requiring Artemis. This obstruction alleviated chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) CHD3.1 dispersal from heterochromatic DSBs; however, how actually adjusted after unknown. In this paper,...
ATM is mutated in the human genetic disorder ataxia telangiectasia, which characterized by ataxia, immune defects, and cancer predisposition. Cells that lack exhibit delayed up-regulation of p53 response to ionizing radiation. Serine 15 phosphorylated <i>in vivo</i> radiation, antibodies immunoprecipitate a protein kinase activity that, presence manganese, phosphorylates at serine 15. Immunoprecipitates also phosphorylate PHAS-I manganese-dependent manner. Here we have purified from cells...