From Genetics to Anti-Tumor Immunity: Exploring Poison Exons, 3' UTRs, and Vault Organelles

Abstract

This work integrates three distinct yet interconnected projects, providing novel insights into genomic regulation, cancer biology, and immunotherapy. The first project reveals the critical role of a ‘poison exon’ in the gene Smndc1, demonstrating that poison exon deletion in mouse and Arabidopsis thaliana models disrupts mRNA processing and impacts organism phenotypes. This highlights the importance of conserved poison exons in molecular and organism fitness. The second project focuses on alternative polyadenylation in melanoma, demonstrating that manipulation of the alternative polyadenylation site of Atg7 alters mRNA stability and ATG7 protein levels and ultimately impacts cell proliferation. This suggests alternative polyadenylation as a potential target in cancer therapy. The final project investigates Major Vault Protein (MVP) in the immune response to cancer, establishing its correlation with improved survival and enhanced response to immune checkpoint blockade in melanoma and renal cell carcinoma. These findings underscore MVP as a promising biomarker and therapeutic target in cancer, illustrating the interconnected nature of molecular mechanisms across diverse biological contexts. All threeprojects collectively underscore the intricate network of genomic mechanisms governing cellular processes, from mRNA processing to immune responses, highlighting the potential for targeted genetic and molecular interventions in advancing cancer therapy and improving patient outcomes.