# Regulation by post-translation modifications in response to stress

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $72,050

## Abstract

Project Summary/Abstract
Ubiquitin ligases (E3s) represent a diverse and conserved group of enzymes, with over 600 members. These
ligases collectively attach the small protein ubiquitin to more than twenty five percent of the proteome, thereby
regulating the stability or activity of each target. Despite the importance of this set of enzymes, only a small
percentage of ubiquitin ligases have well-characterized biological functions. We have conducted a CRISPR
screen examining the sensitivity of mutations of genes encoding human ubiquitin ligases and deubiquitinating
enzymes to a panel of inhibitors covering a broad range of biological pathways. From this screen, we identified
a CUL5 specificity subunit, called WSB2, whose mutation renders cells sensitive to inhibitors of nuclear export
and mitochondrial function. Preliminary studies identified two sets of proteins whose levels are affected by
WSB2: the apoptotic factor BIM and the mRNA export proteins SNIP1 and THRAP3 (two members of the SNARP
complex). In this application, we will determine whether these are independent substrates of the CUL5-WSB2
complex, or alternatively, whether targeting of SNIP1/THRAP3 affects BIM mRNA levels or localization. If
SNIP1 and/or THRAP3 are direct substrates, we will examine the regulation of this ubiquitination event.

## Key facts

- **NIH application ID:** 10801759
- **Project number:** 3R35GM118104-08S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David Paul Toczyski
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $72,050
- **Award type:** 3
- **Project period:** 2016-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801759

## Citation

> US National Institutes of Health, RePORTER application 10801759, Regulation by post-translation modifications in response to stress (3R35GM118104-08S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801759. Licensed CC0.

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