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Impact of splicing factor mutations in the context of tobacco exposure in lung cancer

Institution: University of California, Santa Cruz
Investigator(s): Angela Brooks,
Award Cycle: 2019 (Cycle 29) Grant #: T29KT0401 Award: $736,710
Subject Area: Cancer
Award Type: New Investigator Awards

Initial Award Abstract
Before mRNA molecules direct the synthesis of proteins, intervening segments are removed in a process called splicing, leaving behind the sequences that code for protein. Mutations in genes coding for factors controlling splicing are commonly seen in cancer patients; however, how these mutations contribute to cancer is still unclear. In lung cancer, the splicing factor U2AF1 is frequently mutated in patients with a history of smoking. We seek to understand how this mutation alters the activity of genes associated with lung cancer. Our group and many others have discovered that mutations in U2AF1 lead to many mRNAs that are aberrantly spliced; however, the previous sequencing technology used does not provide the full mRNA sequence nor can we confidently infer which aberrant mRNAs are eventually translated into proteins. In this study, we are using a suite of methods in next-generation sequencing, biochemistry, and molecular and computational biology, to identify the sequences of complete mRNA molecules. In cells with a U2AF1 mutation, we will assess whether aberrantly spliced mRNAs continue to direct the synthesis of proteins and what effect these RNAs have on the activity of cellular processes. We will study the effects of the U2AF1 mutation in two different types of cells to provide clues on which mutation-associated changes contribute to the onset of cancer and which contribute to sustaining or advancing the disease. Given a recent report that the U2AF1 mutation causes enhanced survival of cancer cells during exposure to radiation, we will determine whether cells exposed to cigarette smoke have a growth advantage when they harbor the U2AF1 mutation over cells without that mutation. Lastly, we will focus on the large changes we see in the mutant cells in expression of the uridine phosphorylase gene, UPP1. This gene is known to be highly expressed in lung cancer and our preliminary data shows a shift in favor of more mRNA in the mutant. We will test whether this change in UPP1 mRNA alone supports enhanced survival of cancer cells to damage from tobacco smoke exposure. These findings will advance our understanding of how changes in mRNA processing affect cell function and could lead to novel approaches for treating diseases, including cancers, in which splicing is abnormal.