In the development and progression of cancer, cells frequently delete large regions of DNA that include tumor suppressor genes (TSGs). By virtue of proximity, genes that neighbor TSGs are often co-deleted, which usually does not affect cell fitness. Nonetheless, deletion of a gene as a passenger mutation can make a cancer cell vulnerable to drugs or other mutations in ways that healthy, genetically ?normal? cells are not. Targeting such vulnerabilities to kill cancer cells and leave healthy cells unharmed evokes the genetic principle of ?synthetic lethality.? Two mutations are said to be synthetic lethal when cells tolerate either one individually, but die when they occur together. Thus, identification of genes that are synthetic lethal with co-deleted genes can provide new drug targets. One of the most frequently deleted tumor suppressor genes in cancer is PTEN, which encodes a phosphatase that normally antagonizes cell growth and survival. Only 40 kilobases upstream of the human PTEN locus on chromosome 10q23 is the locus for ATAD1, which encodes an evolutionarily conserved ATPase that is essential for mitochondrial homeostasis. ATAD1 extracts tail-anchored (TA) proteins from the outer mitochondrial membrane (OMM). TA proteins possess a single-pass transmembrane domain at the C- terminus. We conducted a genome-wide CRISPR screen to identify genes that are essential only in the absence of ATAD1, as these would make ideal drug targets for tumors that co-delete ATAD1 with PTEN. Multiple hits from our screen implicate ATAD1 in the regulation of apoptosis, a process that critically depends on TA proteins in the OMM. Specifically, translocation to the OMM by a class of TA proteins known as BH3- only proteins is thought to induce apoptosis. We hypothesize that ATAD1 extracts tail-anchored BH3-only proteins from the outer mitochondrial membrane to prevent aberrant apoptosis. The present proposal describes how we will test this hypothesis using genetics, biochemistry, and animal models. Small molecule mimetics of BH3-only proteins are approved for use in cancer patients, and thus the connection between ATAD1 and apoptosis could have major implications for precision oncology. Together with my sponsors I have generated a research training plan that integrates clinical training and will prepare me for a career as a physician-scientist. My research training plan will help me develop skills in cell biology and biochemistry, which are the specialties of my primary sponsor, Dr. Jared Rutter, and his lab. My clinical training sponsor, Dr. Douglas Grossman, is a physician-scientist and Professor of Dermatology, and he will help me gain clinical experience that emphasizes the diagnosis and treatment of cancer. I will conduct research in the vibrant community of the Department of Biochemistry at the University of Utah, which houses a diverse group of talented investigators dedicated to training young scientists.

Public Health Relevance

Cancer is a leading cause of death in the United States, and this study seeks to identify novel vulnerabilities of a class of particularly lethal tumors, including glioblastoma and prostate cancer. When cancers delete the tumor suppressor gene PTEN, they frequently co-delete a neighboring gene called ATAD1, which is important for mitochondrial protein quality control. We will investigate how loss of ATAD1 may make cancers more likely to activate intracellular signaling pathways that result in cell death, and how this trait could be targeted in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA243440-01A1
Application #
9992410
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2020-04-01
Project End
2025-05-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112