A5042420935- Protein Degradation and Inhibitors
- Acute Myeloid Leukemia Research
- Ubiquitin and proteasome pathways
- Protist diversity and phylogeny
- CRISPR and Genetic Engineering
- Photosynthetic Processes and Mechanisms
- Microtubule and mitosis dynamics
- ATP Synthase and ATPases Research
- Histone Deacetylase Inhibitors Research
- Chronic Myeloid Leukemia Treatments
- FOXO transcription factor regulation
- Mitochondrial Function and Pathology
- Microbial Community Ecology and Physiology
- Autophagy in Disease and Therapy
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Cancer, Lipids, and Metabolism
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Ferroptosis and cancer prognosis
- Genetics, Aging, and Longevity in Model Organisms
- Peptidase Inhibition and Analysis
- Chronic Lymphocytic Leukemia Research
- Signaling Pathways in Disease
Université de Montréal
2012-2025
Institute for Research in Immunology and Cancer
2017-2025
Beth Israel Deaconess Medical Center
2013-2017
Harvard University
2013-2017
University of Pittsburgh
2014
Tumor growth is driven by continued cellular and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs global gene expression makes it therefore an attractive target for cancer therapies. However, what cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear.Here, we address this question. We show that CDK7i, samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic...
To interrogate genes essential for cell growth, proliferation and survival in human cells, we carried out a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 screen B-cell lymphoma line using custom extended-knockout (EKO) library of 278,754 single-guide RNAs (sgRNAs) that targeted 19,084 RefSeq genes, 20,852 alternatively spliced exons, 3,872 hypothetical genes. A new statistical analysis tool called robust analytics normalization knockout screens (RANKS)...
Dinoflagellates are an important component of the marine biota, but a large genome with high–copy number (up to 5,000) tandem gene arrays has made genomic sequencing problematic. More importantly, little is known about expression and conservation these unusual arrays. We assembled de novo catalog 74,655 contigs for dinoflagellate Lingulodinium polyedrum from RNA-Seq (Illumina) reads. The contains 93% EST dataset deposited in GenBank 94% enzymes 16 primary metabolic KEGG (Kyoto Encyclopedia...
The cullin-RING ligases (CRLs) form the major family of E3 ubiquitin ligases. prototypic CRLs in yeast, called SCF enzymes, employ a single E2 enzyme, Cdc34, to build poly-ubiquitin chains required for degradation. In contrast, six different human and enzyme activities, including Cdc34 orthologs UBE2R1 UBE2R2, appear mediate SCF-catalyzed substrate polyubiquitylation vitro. combinatorial interplay these enzymes raises questions about genetic buffering SCFs cells challenges dogma that E3s...
Systematic genetic interaction profiles can reveal the mechanisms-of-action of bioactive compounds. The imipridone ONC201, which is currently in cancer clinical trials, has been ascribed a variety different targets. To investigate dependencies action, we screened genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout library presence either ONC201 or its more potent analog ONC212. Loss mitochondrial matrix protease CLPP intermediate peptidase MIPEP conferred...
Precision in redox signaling is attained through posttranslational protein modifications such as oxidation of thiols. The peroxidase peroxiredoxin 1 (PRDX1) regulates signal transduction changes thiol its cysteines. We demonstrate here that PRDX1 a binding partner for the tumor suppressive transcription factor FOXO3 directly stress response. Heightened oxidative evokes formation disulfide-bound heterotrimers linking dimeric to monomeric FOXO3. Absence enhances nuclear localization and are...
Small-molecule stabilization of weak ubiquitin-enzyme interactions to selectively target the ubiquitin-proteasome system.
Abstract Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase ( TERT ), contributes to age‐associated tissue dysfunction and senescence, p53 plays a crucial role this response. We undertook genome‐wide CRISPR screen identify gene deletions that sensitized p53‐positive human inhibition. uncovered previously unannotated gene, C16ORF72 , which we term Attrition Response 1 TAPR1 exhibited synthetic‐sick relationship loss. A subsequent ‐disrupted reciprocally...
Abstract Although the development of targeted approaches has been effective for treatment B-cell malignancies, outcomes remain poor in relapsed and refractory settings. To expand portfolio B-cell-selective drugs, we developed an interactive computational tool (lymphoblasts.org) identified ferroptosis, a form cell death driven by iron-dependent membrane lipid peroxidation, as previously unrecognized selective vulnerability malignancies. ferroptosis shown potential therapy-resistant tumors, no...
Abstract Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). Although essential in muscle, we identified ETF (ETFDH) one of the most dispensable genes neoplasia, and its expression is reduced across human cancers. caused by decreased ETFDH limits flexibility OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics accelerates neoplastic growth retrograde activation...
Abstract Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). Although essential in muscle, we identified ETF (ETFDH) one of the most dispensable genes neoplasia, and its expression is reduced across human cancers. caused by decreased ETFDH limits flexibility OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics accelerates neoplastic growth retrograde activation...
Polo-like kinase 1 (PLK1) is a serine/threonine required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of have been developed tested in clinical trials. However, these small molecule alone not completely effective. promotes numerous molecular cellular events the cell division cycle it unclear which most crucially depend on activity. We used CRISPR-based genome-wide screening strategy identify genes whose inactivation...
Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We others have previously established bortezomib, a selective proteasome inhibitor, an important potential treatment CML. Here we show that the combined regimens bortezomib with mitotic inhibitors, microtubule-stabilizing agent Paclitaxel PLK1 inhibitor BI2536, efficiently kill TKIs-resistant -sensitive...
Viruses co-opt host proteins to carry out their lifecycle. Repurposed may thus become functionally compromised; a situation analogous loss-of-function mutation. We term such as viral-induced hypomorphs. Cells bearing cancer driver mutations have successfully been targeted with drugs perturbing encoded by the synthetic lethal (SL) partners of cancer-specific mutations. Similarly, SL interactions hypomorphs can potentially be host-based antiviral therapeutics. Here, we use GBF1, which supports...
In many phytoplankton species, cell division (mitosis) usually occurs at defined times of day. This timing is also observed under constant conditions, indicating that it regulated by a circadian clock rather than simple response to the light-dark cycle. For those algae with cycles longer day, opens window opportunity for mitosis particular time day through which cells in an appropriate phase cycle can pass. Although generally studied due ease measurement, some S-phase circadian. thus raises...
CDK7 has a central role in promoting cellular proliferation, through the activation of mitotic CDKs, and by driving global gene expression, targeting RNA polymerase II. Several recently developed inhibitors (CDK7i) have been shown to be non-toxic limit tumour growth for number cancer cell types are now Phase I/II clinical trials. However, mechanisms underlying sensitivity particular cells inhibition remain largely unknown. To improve outcome individual patients increase chances successful...
Our objective was to identify cell surface proteins in the dinoflagellate Lingulodinium polyedrum . Proteins on of living cells that had regions exposed external medium were labeled with Na 125 I. After partial purification membrane and analysis by two‐dimensional gel electrophoresis autoradiography, a protein roughly 43 kDa found have incorporated radiolabel. This cloned using combination microsequencing PCR amplification. The derived sequence cDNA has signal peptide at N‐terminal end thus...
Background information . Mitosis during the dinoflagellate cell cycle is unusual in that nuclear envelope remains intact and segregation of permanently condensed chromosomes uses a cytoplasmic mitotic spindle. To examine regulation context these features, it necessary to isolate characterize regulators such as CDK (cyclin‐dependent kinase). Results We report characterization from Lingulodinium polyedrum This reacts with an anti‐PSTAIRE antibody was identified by protein microsequencing after...