The aim of the research activities detailed in this proposal is to understand how the RNA-binding protein RBM38 mediates the cellular stress response —the series of cellular events triggered by diverse harmful factors to restore cellular homeostasis— by modulating the activity of microRNAs on specific targets. Our objective is to determine the molecular mechanism by which RBM38 interferes with the binding of miRNAs on a selection of messenger RNAs that are targets of the tumor suppressor p53, a protein which guards the genomic integrity and regulates the stress response. The normal cellular stress response is crucial to restore or reprogram various gene-expression patterns that maintain homeostasis. Failure in this response can lead to severe pathological conditions, such as cancer. Understanding the mechanisms that mediate the stress response at the molecular level is thus one of the most important open questions in cell biology today and has a clear impact in molecular medicine and in the pharmaceutical industry.We will use state-of-the-art biophysical techniques to identify the molecular and biophysical basis of RNA recognition by RBM38. We will propose a mechanism to explain how RBM38 controls post-translational gene expression through the inhibition of miRNA activity. Our research will provide the molecular rationale for a key mechanism of cell regulation and will advance our knowledge of the biology involved in the development of cancer. miRNASTRESS will address a gene-regulation mechanism based on the interference of miRNA activity and will provide the necessary structural information to tune the activity of RBM38. Building on our study and on the know-how accumulated on RNA recognition motif-RNA interactions, we aim to use the RBM38 high-resolution structure as a protein template to develop small molecular weight compounds with therapeutic valence that interfere with the RBM38 biological function.