The identification of novel cellular vulnerabilities can be exploited for therapy. For this purpose, we develop innovative genomic and genetic tools and use them to identify cancer vulnerabilities. Key topics are protein production and the non-coding genome.
Pataskar et al., Nature, 2022
Tryptophan depletion results in tryptophan-to-phenylalanine substitutants
Activated T cells infiltrating the tumour microenvironment secrete interferon-γ (IFNγ) that induces expression of the enzyme IDO1 in cancer cells. IDO1 catabolizes tryptophan to subvert T cell immunity. In this paper we showed that despite tryptophan depletion protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process. We coined these W>F peptides ‘substitutants’ to distinguish them from genetically encoded mutants. Substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.
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Champagne et al., Molecular Cell, 2021
Tryptophan depletion results in tryptophan-to-phenylalanine substitutants
Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Such tryptophan shortage conditions stimulate the production of aberrant proteins by ribosomal frameshifting and codon reassignment events at tryptophan codons. We termed this phenomenon “sloppiness in mRNA translation” and strikingly observed its association with hyperactivation of the MAPK pathway. Functionally, sloppiness-induced events can impair protein activity, but also expand the landscape of antigens presented at the cell surface. These aberrant neoepitopes activate T cell responses, and thus can potentially be used to improve tumor immunoreactivity.
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Slobodin et al., Cell, 2017
Transcription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Our study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs.
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Loayza-Puch et al., Nature, 2016
Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently unavailable. In this paper, we harnessed ribosome profiling for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading.
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Korkmaz et al., Nature Biotechnology 2016
Systematic identification of noncoding regulatory elements has, to date, mainly relied on large-scale reporter assays that do not reproduce endogenous conditions. We present two distinct CRISPR-Cas9 genetic screens to identify and characterize functional enhancers in their native context. Our strategy is to target Cas9 to transcription factor binding sites in enhancer regions. We identified several functional enhancer elements and characterized the role of two of them in mediating p53 (TP53) and ERα (ESR1) gene regulation. Moreover, we show that a genomic CRISPR-Cas9 tiling screen can precisely map functional domains within enhancer elements. Our approach expands the utility of CRISPR-Cas9 to elucidate the functions of the noncoding genome.
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