A5021871681- RNA Research and Splicing
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Cytokine Signaling Pathways and Interactions
- Cancer-related molecular mechanisms research
- Cancer Immunotherapy and Biomarkers
- RNA regulation and disease
- Neurobiology and Insect Physiology Research
- Light effects on plants
- T-cell and B-cell Immunology
- Lymphoma Diagnosis and Treatment
- DNA Repair Mechanisms
- Immunotherapy and Immune Responses
- Cell death mechanisms and regulation
- Circadian rhythm and melatonin
- PI3K/AKT/mTOR signaling in cancer
- RNA Interference and Gene Delivery
- CRISPR and Genetic Engineering
- Monoclonal and Polyclonal Antibodies Research
Oncode Institute
2022-2025
The Netherlands Cancer Institute
2022-2025
Hebrew University of Jerusalem
2014-2017
In response to excessive DNA damage, human cells can activate p53 induce apoptosis. Cells lacking still undergo apoptosis upon yet the responsible pathways are unknown. We observed that p53-independent in damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed initiation. A genetic screen identified transfer RNAse SLFN11 kinase GCN2 as factors required for global respectively. Stalled ribosomes...
The majority of mammalian genes contain one or more alternative polyadenylation sites. Choice sites was suggested as the underlying mechanisms for generating longer/shorter transcript isoforms. Here, we demonstrate that mature mRNA transcripts can undergo additional cleavage and at a proximal internal site in 3'-UTR, resulting two stable, autonomous, RNA fragments: coding sequence with shorter 3'-UTR (body) an uncapped downstream point (tail). Analyses human transcriptome has revealed...
Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 cells uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced death (AICD); (2) acute, expansion; (3) chronic, causing dysfunction. Besides established regulators, we...
Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert state" that enhances their visibility the system. Here, we identified alert-state subpopulation of ribosomes defined by presence P-stalk. We show P-stalk (PSRs) formed in response linked tumor immunity, and this is at least partially mediated phosphorylation. PSRs involved preferential translation mRNAs vital for via more efficient transmembrane domains receptor molecules cytokine-mediated...
Highlights•IFNγ-induced tryptophan depletion induces W>F substitutants neoepitopes•W>F neoepitopes are widespread and shared between cancer types•W>F targets of adoptive T cell therapy•Conventional therapy can benefit from targeting neoepitopesSummaryProlonged exposure to interferon-gamma (IFNγ) the associated increased expression enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage in cells, which stimulates ribosomal frameshifting phenylalanine (W>F) codon...
The use of alternative promoters, splicing, and cleavage polyadenylation (APA) generates mRNA isoforms that expand the diversity complexity transcriptome. Here, we uncovered thousands previously undescribed 5′ uncapped polyadenylated transcripts (5′ UPTs). We show these resist exonucleases due to a highly structured RNA N6-methyladenosine modification at their termini. UPTs appear downstream APA sites within host genes are induced upon activation. Strong enrichment in polysomal fractions...
Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK) CYCLE (CYC) initiates the system by promoting rhythmic transcription of hundreds genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for timekeeping. address this issue, we generated flies in which CLK-driven can be reduced partially (approx. 60%) or strongly (90%) without affecting average...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to inhibitors remain major clinical challenges. Here, we show that MYC activation drives mTOR (mTORi) in cancer. Multiomic profiling mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications acquired mTORi AZD8055. was associated with biological processes linked counteracted mTORi-induced translation...
Abstract Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications often altered cancer support cellular transformation. In conditions of limiting levels amino acids, control protein synthesis leads aberrant production the form ribosomal frameshifting or misincorporation non-cognate acids. Here, we studied leucine, an essential acid...
Later stages of apoptotic cell death are characterized by the fragmentation cellular DNA (1). For example, HeLa cells exposed to a lethal dose UVC irradiation (30 J/m2) undergo apoptosis and exhibit (2). fragmentation, which results in reduced content, can be assessed using several methods, most common being analysis flow cytometry. The standard measure for level response tested treatment is fraction with sub-G1 indicating that these underwent loss (3). However, content reached only after...
Abstract mRNA transcripts have limited potential for protein synthesis, defined by their open reading frames 1 . However, recent advances revealed a far more complex reality, in which the proteome exceeds perceived limits of transcriptome 2–6 exposing significant gap our understanding. Our prior studies demonstrated that can undergo further processing, yielding truncated, uncapped mRNAs with translation 2,7 Yet, biological importance this process remains mostly unclear. Here, we demonstrate...
The translation of an mRNA transcript is traditionally thought to be limited its open reading frames. However, recent findings reveal a more complex reality in which the proteome vastly exceeds transcriptome limits. Here, we demonstrate that JAK1 can cleaved into truncated, uncapped form with shorter ORF, leading JH1 kinase domain independently other domains, process term 'RNA dicing'. Canonical and diced variants differently impact cell proliferation tumorigenesis, balance these isoforms...
Abstract Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an “alert-state” that enhances their visibility the system. Here, we identified subpopulation of ribosomes (ASRs) defined by presence P-stalk. We show ASRs formed in response linked tumor immunity, and involved preferential translation mRNAs vital for response. Mechanistically, required efficient transmembrane domains receptor molecules cytokine-mediated processes. Importantly, loss ASR...