# CRL3KEAP1 complex licenses genotoxic stress-induced tumor cell death

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $182,909

## Abstract

PROJECT SUMMARY/ABSTRACT
This application is responsive to PA-17-449: The Interplay of Cell Death Pathways in Cancer Cell
Survival and Resistance to Therapy (R21). In general, genotoxic stress triggers apoptosis if tumor
cells express functional p53. Genotoxic stress can also induce p53 independent apoptosis due to
the auto-depletion of XIAP and cIAP1/2, which leads to the formation of “ripoptosome” complex.
Ripoptosome can stimulate caspase-8-mediated apoptosis. Mutated p53 and caspase-8 have
been frequently detected in human cancers. Caspase-8 mutation or inactivation often leads to
resistance to apoptosis. However, in a few cases, it renders cells highly susceptible to another
form of programmed cell death, termed “necroptosis.” Kinase RIPK3 and its substrate MLKL are
the critical players for necroptosis. Although several studies have indicated that DNA damage can
induce necroptosis (or undefined necrosis), the molecular mechanism is largely unknown. Herein,
we have used an unbiased genome-wide CRISPR knockout approach to identify new players in
DNA damage-induced necroptosis. We identified Cullin3 (Cul3)-RING E3 ubiquitin Ligase
(CRL3KEAP1) complex as a promising candidate that mediated DNA damage-induced necroptosis.
Our working model is that CRL3KEAP1 complex needs to degrade an unidentified substrate(s) to
let the progression of DNA damage-induced necroptosis, thus licensing genotoxicity-induced cell
death. We will make efforts to test this hypothesis in this proposal. We will determine what the
CRL3KEAP1 substrate(s) is(are) and how it(they) can halt cell death. The proposed studies will
provide new mechanistic insights on DNA damage agents induced cell death. Our ongoing efforts
have the potential to change how we trigger cell death in tumors, especially in those with p53,
caspase-8, and/or KEAP1 mutations.

## Key facts

- **NIH application ID:** 10189885
- **Project number:** 1R21CA259457-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yi-Nan Gong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,909
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189885

## Citation

> US National Institutes of Health, RePORTER application 10189885, CRL3KEAP1 complex licenses genotoxic stress-induced tumor cell death (1R21CA259457-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10189885. Licensed CC0.

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