A5016348964- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Endoplasmic Reticulum Stress and Disease
- Cancer, Hypoxia, and Metabolism
- DNA Repair Mechanisms
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Telomeres, Telomerase, and Senescence
- RNA regulation and disease
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Cancer-related gene regulation
- Cancer Cells and Metastasis
- Epigenetics and DNA Methylation
- Tryptophan and brain disorders
- 14-3-3 protein interactions
- Autophagy in Disease and Therapy
- Receptor Mechanisms and Signaling
- Adenosine and Purinergic Signaling
- Genetic Neurodegenerative Diseases
- Aldose Reductase and Taurine
Western University
2017-2024
Structural Genomics Consortium
2023-2024
University of Toronto
2023-2024
Robarts Clinical Trials
2022
Midwestern University
2021
Google (United States)
2017
The multi-subunit C-terminal to LisH (CTLH) complex is the mammalian homologue of yeast Gid E3 ubiquitin ligase complex. In this study, we investigated human CTLH and characterized its activity. We confirm that immunoprecipitated from cells comprises RanBPM, ARMC8 α/β, muskelin, WDR26, GID4 RING domain proteins RMND5A MAEA. find loss expression individual subunits compromises stability other members MAEA protein levels are interdependent. Using in vitro ubiquitination assays, demonstrate has...
Abstract Ubiquitination is an essential post‐translational modification that regulates protein stability or function. Its substrate specificity dictated by various E3 ligases. The human C‐terminal to LisH (CTLH) complex a newly discovered multi‐subunit really interesting new gene (RING) ligase with only few known ubiquitination targets. Here, we used mass spectrometry‐based proteomic techniques gain insight into CTLH function and substrates in HeLa cells. First, global proteomics determined...
ABSTRACT The C-terminal to LisH (CTLH) complex is a newly discovered multi-subunit E3 ubiquitin ligase and its cellular functions are poorly characterized. Although some CTLH subunits have been found localize in both the nucleus cytoplasm of mammalian cells, differences between compartment-specific complexes not explored. Here, we show that forms different molecular mass nuclear cytoplasmic fractions. Loss WDR26 severely decreased subunit levels impaired higher-order formation, revealing as...
Abstract The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) Dementia with Lewy bodies (DLB). Molecular chaperones play important roles diseases members of the chaperone machinery are often deposited bodies. Here, we show that Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, co-deposited Hsp70 insoluble fractions two mouse models misfolding. also co-localized...
Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline Alzheimer's disease (AD). Recently, we identified a quinone reductase 2 (QR2) pathway in brain, which QR2 acts removable memory constraint buffer within neurons. becomes overexpressed with age, it possibly novel contributing to age-related deficit. We found that, human cells, genetic removal of produced shift proteome opposing that AD brains while simultaneously...
Abstract Here we describe ProtacID, a flexible BioID (proximity-dependent biotinylation)-based approach to identify PROTAC-proximal proteins in living cells. ProtacID analysis of VHL- and CRBN-recruiting PROTACs targeting number different (localized chromatin or cellular membranes, tested across six human cell lines) demonstrates how this technique can be used validate PROTAC degradation targets non-productive ( i . e non-degraded) PROTAC-interacting proteins, addressing critical need the...
Abstract The CTLH complex is a multi-subunit ubiquitin ligase that recognizes substrates with Pro/N-degrons via the substrate receptor GID4. Recently, focus has turned to this as potential mediator of targeted protein degradation, but role GID4-mediated ubiquitylation and proteasomal degradation plays in humans thus far remained unclear. Here, we report PFI-7, potent, selective, cell-active chemical probe antagonizes Pro/N-degron binding human Use PFI-7 proximity-dependent biotinylation...
c-Raf is a central component of the extracellular signal-regulated kinase (ERK) pathway which implicated in development many cancer types. RanBPM (Ran-Binding Protein M) was previously shown to inhibit expression, but how this achieved remains unclear. part recently identified E3 ubiquitin ligase complex, CTLH (C-terminal LisH) complex. Here, we show that complex regulates expression through control its degradation. Several domains were found necessary regulate levels, only C-terminal CRA...
Histone deacetylase 6 (HDAC6) is a microtubule-associated that promotes many cellular processes lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) HDAC6 found RanBPM expression inhibits activity. part of putative E3 ubiquitin ligase complex, termed the C-terminal LisH (CTLH) complex. Here, we investigated involvement CTLH complex on inhibition assessed outcome this regulation motility induced by HDAC6.Cell lines...
The Ku70/80 heterodimer is a key player in non-homologous end-joining DNA repair but involved other cellular functions like telomere regulation and maintenance, which Ku's role not fully characterized. It was previously reported that knockout of Ku80 human cell line results lethality, the underlying cause Ku essentiality cells has yet to be explored. Here, we established conditional Ku70 using CRISPR/Cas9 editing study function. While observed loss viability upon depletion, did detect...
Abstract The Pro/N-degron recognizing C-terminal to LisH (CTLH) complex is an E3 ligase of emerging interest in the developmental field and for targeted protein degradation (TPD) modalities. human CTLH forms distinct supramolecular ring-shaped structures dependent on multimerization WDR26 or muskelin ß-propeller proteins. Here, we find that, cells, activity dictated by a dynamic exchange between tandem with autoregulation. Proteomic experiments revealed that complex-associated turnover major...
The Pro/N-degron recognizing C-terminal to LisH (CTLH) complex is an E3 ligase of emerging interest in the developmental biology field and for targeted protein degradation (TPD) modalities. human CTLH forms distinct supramolecular ring-shaped structures dependent on multimerization WDR26 or muskelin β-propeller proteins. Here, we find that, HeLa cells, activity dictated by interplay between tandem with autoregulation. Proteomic experiments revealed that complex-associated turnover a major...
In this review, we explore the current landscape of preclinical and clinical therapeutics targeting epigenetic complexes in cancer, focusing on targets with enzymatic inhibitors, degraders, or ligands capable disrupting protein–protein interactions. Current strategies face challenges such as limited single-agent efficacy due to insufficient disruption chromatin incomplete dissociation from chromatin. Further complications arise adaptability cancer cell and, some cases, dose-limiting...
Abstract The Ku70/80 heterodimer is a key player in non-homologous end-joining DNA repair but has also been involved other cellular functions like telomere regulation and maintenance, which Ku’s role not fully characterized. It was previously reported that knockout of Ku80 human cell line results lethality, the underlying cause Ku essentiality cells yet to be explored. Here, we established conditional Ku70 study function. Endogenous achieved using CRISPR/Cas9 editing where expression...
The C-terminal to LisH (CTLH) complex is a tumour-suppressive E3 Really Interesting New Gene (RING) ubiquitin ligase that regulates intracellular signaling pathways and maintains cellular homeostasis. It comprised of 8 individual proteins have been shown mediate variety protein-protein interactions; these proteins, Required for Meiotic Division 5 Homolog A (RMND5A) Macrophage Erythroblast Attacher (MAEA) contain the RING domains required CTLH transfer specific protein substrates. Although...