The integrated stress response (ISR) reprograms cellular gene expression to promote survival until transient stresses have passed. A major aim of the ISR is to redirect cellular energy reserves from pro-growth pathways towards pro-survival pathways. As biogenesis of ribosomes is an incredibly energy intensive task and mass production of new ribosomes are most needed during growth, it is not surprising that ribosome biogenesis is regulated during stress. However, how this regulation is accomplished and how it is intertwined with the ISR is unknown. Ribosomes are composed of 4 non-coding RNAs (rRNAs) and 80 ribosomal proteins (RPs). Proper coordination of rRNA and RP synthesis is critical to cellular homeostasis. Therefore, the ISR must co-regulate rRNA and RP synthesis during cellular stress. Failure to do so would only further compound the cellular insult. Data presented here identifies angiogenin (ANG) as a major regulator of ribosome biogenesis during ISR. We previously identified ANG as the protein that cleaves tRNAs during ISR to produce a set of novel small RNAs called tRNA-derived stress-induced RNAs (tiRNAs). We have shown that tiRNAs inhibit translation during a stress response and that Y-box binding protein 1 (YB1) is involved in this pathway. Data presented here shows that a 2nd protein, cellular nucleic acid binding protein (CNBP), is also a component of this pathway. We also show that during a stress response, tiRNAs specifically regulate the translation of RPs. Further, we demonstrate that YB1 has a role in RP biosynthesis. Finally, in unstressed cells, ANG promotes the expression of rRNA via an unknown mechanism. Data presented here suggests that ANG is an rRNA processing enzyme and, upon activation of the ISR, rRNA processing is inhibited. This allows for co-regulation of RP and rRNA synthesis. This proposal will study 1) How tiRNAs specifically regulate RP translation under stress, 2) Determine the role that YB1 plays in ribosome biogenesis and 3) Show how rRNA processing is regulated under stress and determine the role ANG plays in this process.
The proposed work will provide a better understanding of the basic molecular mechanisms that allow cells to survive and grow in adverse environmental conditions. Our lab has previously identified angiogenin, a ribonuclease implicated in cancer cell proliferation and neurodegeneration, as a protein critical stress responsive protein. Here, I aim to determine angiogenin promotes cell survival with aims at producing treatments and cures for cancers and neurodegeneration.