Project description:We report a modulated expression of tRNA fragments and microRNAs linked to chondrosarcoma progression and demonstrate a method for re-modulating this pathway
Project description:Transfer RNAs (tRNAs) are subject to numerous posttranscriptional modifications that influence their maturation, stability, and function. Adenosine to Inosine (A-to-I) editingin thetRNA anticodon stem loop is an important modification that influences anticodon-codon recognition.However,the implications of tRNA editing in cancer and its potential for diagnostic and therapeutic applicationsare not yet well understood.We showed that the ADAT2/3 enzyme complex, responsible for this modification in humans, is amplified and overexpressed in several tumor types,with a higher amplification rate in sarcoma tumors, particularly liposarcomas. We determine that the ADAT complex works as an oncogene in these tumors and that its inhibition reduces tumor growth, offering a new approach to cancer treatment. In addition, we provided insight into the mechanisms of cancer development and progression, demonstrating that tRNA editing is required for higher mRNA translation of oncogenic proteins enriched with specific ADAT-sensitive codons. Thus, ADAT-mediated tRNA modification drives oncogenic transformation by remodeling the set of mRNAs being actively translated to increase expression of proteins that promote proliferation. Our results explain how cancer cells benefit from increased tRNA A-to-I editing and propose ADATs as potential therapeutic targets for the treatment of cancer.
Project description:The cancer cells selectively promote the translation of specific oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here we found that tRNA m7G methyltransferase complex components METTL1/WDR4 were both upregulated in HNSCC and associated with poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced m7G levels of 16 tRNAs, causing translational inhibition of a subset of oncogenic transcripts, including the genes related to PI3K/AKT/mTOR signaling pathway. In addition, chemical modulators of PI3K/AKT/mTOR signaling pathway can reverse the effects of Mettl1 in HNSCC. Furthermore, single-cell RNA sequencing results revealed that depletion of Mettl1 in tumor cells altered the immune landscape and cell-cell interaction between tumor and stromal compartment. In summary, this study uncovered the physiological function and mechanism of mis-translation regulation mediated by tRNA m7G modification in HNSCC, and suggested that targeting METTL1 could be a promising treatment strategy for HNSCC patients.
Project description:The human genome encodes hundreds of tRNA genes but their individual contribution to the tRNA pool is not fully understood. Deep sequencing of tRNA transcripts (tRNA-Seq) can estimate tRNA abundance at single gene resolution, but tRNA structures and post-transcriptional modifications impair these analyses. Here we present a bioinformatics strategy to investigate differential tRNA gene expression and use it to compare tRNA-Seq datasets from cultured human cells and human brain. We find that sequencing caveats affect quantitation of only a subset of human tRNA genes. Unexpectedly, we detect several cases where the differences in tRNA expression among samples do not involve variations at the level of isoacceptor tRNA sets (tRNAs charged with the same amino acid but using different anticodons); but rather among tRNA genes within the same isodecoder set (tRNAs having the same anticodon sequence). Because isodecoder tRNAs are functionally equal in terms of genetic translation, their differential expression may be related to non-canonical tRNA functions. We show that several instances of differential tRNA gene expression result in changes in the abundance of tRNA-derived fragments (tRFs) but not of mature tRNAs. Examples of differentially expressed tRFs include: PIWI-associated RNAs, tRFs present in tissue samples but not in cells cultured in vitro, and somatic tissue-specific tRFs. Our data support that differential expression of tRNA genes regulate non-canonical tRNA functions performed by tRFs.