# Mitochondrial quality control as a selective vulnerability in cancers with chromosome 10q deletion

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $51,752

## Abstract

PROJECT ABSTRACT
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.

## Key facts

- **NIH application ID:** 10357943
- **Project number:** 5F30CA243440-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jacob Michael Winter
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357943

## Citation

> US National Institutes of Health, RePORTER application 10357943, Mitochondrial quality control as a selective vulnerability in cancers with chromosome 10q deletion (5F30CA243440-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10357943. Licensed CC0.

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