tRNA modification reprogramming and translational remodeling in cancer

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

Abstract

Project summary Over 300 different chemical modifications on RNA have been identified and this ‘epitranscriptome’ plays important roles in the posttranscriptional control of gene expression. Dysregulation of certain RNA-modifying enzymes including RNA methyltransferases (MTases) is linked to cancer initiation and progression, and new evidence suggests these may provide a new class of druggable targets for treating various cancer types. Transfer RNA (tRNA) functions in deciphering the genetic code in mRNAs via codon-anticodon interactions and is one of the most heavily modified RNA species in cells. The diverse and numerous chemical modifications of the anticodon and main body of tRNAs are critical for tRNA integrity and function, thereby affecting protein synthesis. This project will provide major new insight into the role of tRNA modification reprograming and translational remodeling in cancer and cellular stress responses. RNA mass spectrometry and sequencing approaches will be used to comprehensively catalogue tRNA modification and expression dynamics during melanoma progression and metastasis using both human patient-derived xenografts and clinical samples. An innovative new methodology for enhanced Ribosome profiling will be deployed to correlate RNA modification changes with cancer-associated translational remodeling at codon resolution. Functional screening of all >600 human tRNA genes will be performed to identify individual tRNA genes involved in various stress response pathways in cancer cells, as well as tumorigenesis and metastasis in vivo. The role of several tRNA-modifying enzymes and individual tRNAs in melanoma progression and stress response pathways will be investigated, and RNA mass spectrometry, tRNA sequencing, Ribo-seq, and proteomic studies will be used to reveal the underlying molecular and cellular mechanisms linked to cancer initiation, progression, and metastasis.