Characterization of tiRNA-mediated Translational Repression

Brigham And Women'S Hospital, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Cell survival pathways allow cells to survive in stressful environments until transient stresses have passed. This is critical for the survival of normal cells, but also plays a role in the growth of tumors and is hyperactive in various inflammatory diseases. We have discovered a novel stress response pathway that is dependent upon angiogenin (ANG), a 14 kDa member of the pancreatic ribonuclease superfamily, which enhances cell survival and proliferation. ANG has been found to be among the most highly upregulated proteins in prostate and other cancers as well as other diseases including irritable bowel syndrome. It is also mutated in a subset of patients with amyotrophic lateral sclerosis (ALS) and parkinson's disease. The purpose of the proposed work is to dissect the mechanisms and molecular details of this pathway. This knowledge will prove critical in our understanding of how ANG promotes cell survival and proliferation and will identify druggable targets for cancer and ALS treatments. ANG targets and cleaves tRNAs in the anti-codon loop to produce tRNA-derived stress- induced RNAs (tiRNAs). A subset of 5', but not 3', tiRNAs are able to inhibit translation of uncapped>capped>IRES containing mRNAs in cell free systems. Bioactive tiRNAs interact with two proteins, Y-box Binding protein 1 (YB-1) and Cytoplasmic Nucleic acid binding protein (CNBP). The hypotheses presented in this proposal address the molecular mechanisms by which ANG/tiRNAs reprogram cellular translation to promote cell growth and proliferation. This proposal will determine how newly discovered tiRNAs are able to inhibit translation and then determine which mRNAs they target in cells. I will determine the extent to which CNBP and YB-1 are required for translation inhibition. Then, I will determine the level to which tiRNAs are able to promote survival in cells in response to various cell stresses. I will also investigate how tiRNAs promote increased proliferation and metastatic potential in breast cancer cells. I hypothesize that translation attenuation inhibits the translation of many housekeeping mRNAs while upregulating the translation of mRNAs encoding proteins with pro-growth and cytoprotective activities. The completion of these aims will result in a better understanding of how cells are able to survive and proliferate in adverse environments. This will result in the identification of targets to inhibit this pathway to prevent cell growth.