A5079044371- DNA Repair Mechanisms
- Chronic Lymphocytic Leukemia Research
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- Cancer-related Molecular Pathways
- Retinal Development and Disorders
- Cancer therapeutics and mechanisms
- Lymphoma Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- Genetic Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Carcinogens and Genotoxicity Assessment
- CRISPR and Genetic Engineering
- Immunodeficiency and Autoimmune Disorders
- Neurogenesis and neuroplasticity mechanisms
- Biochemical and Molecular Research
- Chromosomal and Genetic Variations
- Cell death mechanisms and regulation
- Radiomics and Machine Learning in Medical Imaging
- Integrated Circuits and Semiconductor Failure Analysis
- PI3K/AKT/mTOR signaling in cancer
- Glioma Diagnosis and Treatment
University of Manitoba
2015-2025
CancerCare Manitoba
2016-2025
Research Institute in Oncology and Hematology
2015-2023
McMaster University
2023
Jamia Hamdard
2022
Institute of Medical Sciences
2022
St. Jude Children's Research Hospital
2006-2014
University of Alberta
2002-2011
Ducks Unlimited
2011
Johnson University
2009
Nonhomologous end-joining (NHEJ) is the primary DNA repair pathway thought to underlie chromosomal translocations and other genomic rearrangements in somatic cells. The canonical NHEJ pathway, including ligase IV (Lig4), suppresses instability translocations, leading notion that a poorly defined, alternative (alt-NHEJ) generates these rearrangements. Here, we investigate requirement of translocation formation mouse Mammals have two ligases, Lig1 Lig3, addition Lig4. As deletion Lig3 results...
Ataxia oculomotor apraxia-1 (AOA1) is an autosomal recessive neurodegenerative disease that results from mutations of aprataxin (APTX). APTX associates with the DNA single- and double-strand break repair machinery able to remove AMP 5'-termini at strand breaks in vitro. However, attempts establish a defect APTX-defective cells have proved conflicting unclear. We reasoned this may reflect 5'-AMP represent only minor subset induced cells, and/or availability alternative mechanisms for removing...
Aprataxin, defective in the neurodegenerative disorder ataxia oculomotor apraxia type 1, resolves abortive DNA ligation intermediates during repair. Here, we demonstrate that aprataxin localizes at sites of damage induced by high LET radiation and binds to mediator DNA-damage checkpoint protein 1 (MDC1/NFBD1) through a phosphorylation-dependent interaction. This interaction is mediated via FHA domain multiple casein kinase 2 di-phosphorylated S-D-T-D motifs MDC1. X-ray structural mutagenic...
DDX1 bodies, cleavage Cajal bodies (CBs), and gems are nuclear suborganelles that contain factors involved in RNA transcription and/or processing. Although all four can exist as distinct entities, they often colocalize or overlap with each other. To better understand the relationship between these we examined their spatial distribution a function of cell cycle. Here, report whereas CBs present throughout interphase, CPSF-100-containing predominantly found during S G2 phases,...
Ataxia oculomotor apraxia 1 (AOA1) results from mutations in aprataxin, a component of DNA strand break repair that removes AMP 5' termini. Despite this, global rates chromosomal are normal variety AOA1 and other aprataxin-defective cells. Here we show short-patch single-strand (SSBR) cell extracts bypasses the point aprataxin action at oxidative breaks stalls final step ligation, resulting accumulation adenylated nicks. Strikingly, this defect insufficient levels nonadenylated ligase, SSBR...
The pathogenesis of inherited genome instability neurodegenerative syndromes remains largely unknown. Here, we report new disease-relevant murine models instability–driven neurodegeneration involving disabled ATM and APTX that develop debilitating ataxia. We show ataxia result from transcriptional interference in the cerebellum via aberrant messenger RNA splicing. Unexpectedly, these splicing defects were restricted to only Purkinje cells, disrupting expression critical homeostatic...
Multiple lines of evidence support the notion that DNA ligase III (LIG3), only found in mitochondria, is essential for viability both whole organisms and cultured cells. Previous attempts to generate cells devoid mitochondrial failed. Here, we report, first time, derivation viable LIG3-deficient mouse embryonic fibroblasts. These lack mtDNA are auxotrophic uridine pyruvate, which may explain apparent lethality Lig3 knock-out observed previous studies. Cells with severely reduced expression...
The BH3-only family member BNIP3 has been described as either promoting cell survival or death. This depends upon the level of expression and its cellular localization. Increased under hypoxia contributes to death through increased mitochondrial dysfunction. Furthermore, mice lacking show inhibition ischemic cardiomyocyte apoptosis. In contrast, nuclear localization blockage apoptosis in glioma cells repression pro-apoptotic genes. We have discovered that mouse embryonic fibroblasts (MEFs)...
DNA strand break repair is essential for the prevention of multiple human diseases, particularly those which feature neuropathology. To further understand pathogenesis these syndromes, we recently developed animal models in single-strand (SSBR) components, XRCC1 and Ligase III (LIG3), were inactivated developing nervous system. Although biochemical evidence suggests that inactivation LIG3 should share common biological defects, found profound phenotypic differences between two models,...
PTEN mutation occurs in a variety of aggressive cancers and is associated with poor patient outcomes. Recent studies have linked mutational loss to reduced RAD51 expression function, key factor involved the homologous recombination (HR) pathway. However, these remain controversial, as they fail establish definitive causal link that PTEN-dependent, while other not been able recapitulate relationship between RAD51/HR function. Resolution this apparent conundrum essential due...
Background The Reelin-Dab1 signaling pathway plays a critical role in the positioning of migrating neurons, dendrite formation and lamination developing central nervous system. We have previously identified two alternatively spliced forms Dab1 chick retina: an early form, Dab1-E, expressed retinal progenitor cells, late or Dab1-L, amacrine ganglion cells. Compared to Dab1-E lacks exons that encode Src family kinase (SFK) phosphorylation sites. Principal Findings Both Dab1-L Dab1-E-like...