# Elucidating the Role of C16orf72 in the Cellular Stress Response Network

> **NIH NIH F30** · NORTHWESTERN UNIVERSITY · 2024 · $53,974

## Abstract

PROJECT SUMMARY
A hallmark of cancer is the ability of malignant cells to maintain viability in the face of stressors such as
aneuploidy, nutrient scarcity, and xenobiotic compounds. This multi-stress-resilience phenotype enables tumor
formation, metastasis, and therapy resistance. Individual molecular pathways co-opted by cancer cells to
promote stress resilience have been thoroughly characterized, but how these specialized pathways are
integrated in complex physiological stress states remains poorly understood. Recently, we used genome-scale
fitness screening data to estimate the intrinsic stress phenotype of 689 diverse cancer cell and identify genes
which are selectively essential in cancer cells highly reliant on multiple distinct stress response pathways.
Through our integrative analysis, we discovered C16orf72, a previously uncharacterized protein which is broadly
stress-inducible and promotes resilience to mechanistically diverse stress insults. We have determined that
C16orf72 physically interacts with HUWE1, an E3 ligase known to ubiquitinate proteins involved in stress
response pathways. Moreover, loss of either C16orf72 or HUWE1 produces highly similar transcriptomic and
ubiquitination phenotypes while not affecting expression of the other factor. Thus, our overarching hypothesis is
that C16orf72 mediates stress resilience by physically interacting with HUWE1 to promote HUWE1-mediated
ubiquitination of proteins with critical roles in diverse stress response pathways. In Aim 1 of this proposal, we will
define the binding interface of C16orf72 and HUWE1 and test several non-exclusive models by which C16orf72
regulates HUWE1 enzymatic activity. In Aim 2, we will determine the substrates and specific modifications which
underly the role of C16orf72 and HUWE1 in cellular stress resilience and canonical stress response signaling.
In Aim 3, we will determine the extent to which C16orf72 is required for in vivo tumorigenesis and the
development of therapy resistance in breast cancer. The long-term goals of the proposed work are to determine
the molecular mechanism by which C16orf72 promotes cellular stress resilience and investigate the therapeutic
potential of blocking the C16orf72/HUWE1 axis in cancer cells.

## Key facts

- **NIH application ID:** 10798252
- **Project number:** 5F30CA264513-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Russell Amici
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798252

## Citation

> US National Institutes of Health, RePORTER application 10798252, Elucidating the Role of C16orf72 in the Cellular Stress Response Network (5F30CA264513-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10798252. Licensed CC0.

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