# pSer784-VCP: a clinically relevant link between autophagy and DNA damage response

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $220,894

## Abstract

PROJECT SUMMARY
Autophagy and DNA damage response (DDR) are two evolutionarily conserved, fundamentally important
cellular programs. Both can be deregulated in cancer and in turn targeted as cancer therapies. Despite
compelling evidence that autophagy and DDR are connected, the scarce number of known DDR-relevant
autophagy targets greatly limits our understanding of their functional crosstalk. Mixed reports regarding the
chemotherapy-sensitizing effect of autophagy activation strongly suggest the context-dependency of the
physiological role of autophagy in DDR. We hypothesize that this context-dependency could be determined by
the functional importance of the affected autophagy targets for DDR. In this grant, we focus on an important
DDR factor named VCP. VCP is a ubiquitously expressed AAA+ ATPase which recognizes polyubiquitinated
proteins and facilitates their degradation by both the ubiquitin-proteasome and autophagy/lysosome pathways.
Our recent work showed that DNA damage-induced Ser784 phosphorylation selectively increases nuclear VCP
function for DDR. Importantly, pSer784-VCP is poor prognostic marker for chemotherapy-treated breast cancer
patients. These data suggest that targeting pSer784-VCP may be a novel and effective chemo-sensitizing
approach. In this grant, we present preliminary data showing that pSer784-VCP may be a previously
unrecognized target of autophagy. In Aim 1, we will define the specific autophagy pathway that is involved in
pSer784-VCP degradation and seek for direct evidence that pSer784-VCP undergoes nuclear export upon
DNA damage. In Aim 2, we will test in a large panel of triple-negative breast cancer cell lines whether DNA
damage-induced pSer784-VCP levels predict chemo-sensitizing effects of autophagy modulators. Together,
these experiments will improve our understanding of the functional crosstalk between autophagy and DDR,
and help define the biological context within which co-targeting of these two cellular programs can be
therapeutically beneficial.

## Key facts

- **NIH application ID:** 10435173
- **Project number:** 1R21CA263435-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jieya Shao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $220,894
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435173

## Citation

> US National Institutes of Health, RePORTER application 10435173, pSer784-VCP: a clinically relevant link between autophagy and DNA damage response (1R21CA263435-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10435173. Licensed CC0.

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