LSM1 AND RNY1: CLUES IN THE SEARCH FOR HOW RNA METABOLIC PATHWAYS CONTROL CANCER

Abstract

Carcinogenesis requires numerous alterations to gene expression to evade normal controls on cellular growth, invasion, and immortality. Traditionally, these changes have been examined in the context of deregulated transcriptional control of oncogenes and tumor suppressors. However, in recent years, research has revealed that processes outside of transcription such as RNA splicing, translation, and decay are also deregulated in cancers, sustaining tumorigenic potential. This dissertation details our investigation into the cellular functions of two RNA metabolic proteins whose human orthologs are deregulated in tumors: a putative oncogene, Lsm1, and a putative tumor suppressor, Rny1. Herein, we reveal interesting functions for these proteins that might provide insight into their roles in carcinogenesis. First, we demonstrate a role for Lsm1 over-expression in altered splicing through depletion of U6 snRNA levels. Second, we clarify the mechanism for Rny1's activity against RNA substrates and identify cis regions required for its non-catalytic role in growth inhibition. Overall, this knowledge expands our understanding of how RNA metabolism might be deregulated in cancer and could provide novel pathways to target for synthetic lethal responses in cancers with altered expression of these proteins.