Role of NIAM, A Putative Cancer Gene, in Chromosomal Instability and Glioblastoma

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DESCRIPTION (provided by applicant): Uncontrolled cellular proliferation, altered p53 tumor suppressor signaling, and chromosomal instability (CIN) are signature features of tumorigenesis. My thesis laboratory discovered a new activator of p53 signaling called NIAM (Nuclear Interactor of ARF and Mdm2). NIAM is a novel protein that prevents CIN and inhibits cell proliferation, and its mRNA is reduced in human cancers such as glioblastoma multiforme (GBM). NIAM has functional connections with ARF, Mdm2 and p53 yet it can suppress proliferation and CIN independent of all three factors. Thus, NIAM functions in multiple anti-cancer pathways. How NIAM maintains chromosome stability and its significance in cancer are unknown. A major cause of CIN is faulty DNA damage repair. Our preliminary data reveal NIAM is a chromatin-associated protein that localizes to DNA repair foci, enhances the DNA damage response, and binds the histone acetyltransferase Tip60. Like NIAM, Tip60 binds chromatin, activates p53 and interacts functionally with ARF and Mdm2. Tip60 can also act independently of ARF-Mdm2- p53 to activate DNA damage checkpoints, promote DNA repair, and maintain chromosome stability. Based on these observations, I hypothesize that NIAM is a tumor suppressor that inhibits CIN and cancer through its interaction with Tip60 and/or promoting DNA repair. Three aims are proposed to test that hypothesis and define the biological function of NIAM using complementary molecular, biological and genomic approaches. Aim 1: Determine if NIAM maintains chromosomal stability through chromatin association and DNA damage repair. Aim 2: Define the molecular basis and significance of NIAM-Tip60 association. Aim 3: Determine if there is a link between NIAM loss, CIN and cancer. These studies are novel and significant because they will define the mechanisms by which NIAM, a putative tumor suppressor, maintains chromosomal stability and thus genomic integrity. Experiments (Aim 3) also explore the significance of altered NIAM expression and CIN in GBM, the most aggressive and prevalent type of adult brain cancer. This work may improve the diagnosis and treatment of GBM, a deadly cancer which still lack effective therapies. Importantly, this is a multi-disciplinar thesis project that will greatly advance my skills in molecular cell biology and teach me how to study the mechanisms, biology and genomics of cancer. My ultimate goal is to become an independent physician scientist studying pediatric cancers. I am excited that this training experience will effectively prepare me for such a career in translational cancer research.