# Mechanistic Analysis of the Ubiquitin-Proteasome System

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2024 · $64,373

## Abstract

Project Summary / Abstract
The ubiquitin-proteasome system (UPS) regulates the activity, localization and stability of thousands of
proteins in the cell. By catalyzing the covalent attachment or removal of ubiquitin to target proteins, the
enzymes of the UPS regulate virtually every cellular process, including cell signaling, cell survival and cell
division. The widespread influence of the UPS on biology also has important consequences for human health,
as mutations in components of the UPS cause diseases such as cancer. Encouragingly, the vast number of
enzymes and protein-protein interactions in the UPS are also providing new drug targets to treat disease.
There is growing interest in developing drugs that either inhibit the UPS or harness its ability to eliminate
harmful proteins. For these reasons, mechanistic studies of the UPS have the potential to reveal new insights
into biological regulation and may also help us understand mechanisms of disease pathogenesis and reveal
opportunities for therapy.
The focus of this proposal is to discover new substrates of the UPS and to characterize the specificity and
regulation of enzymes that add and remove ubiquitin to these proteins. Although many components of the UPS
are well-studied, we still have little insight into the molecular targets for hundreds of UPS enzymes encoded in
the genome. This study will help fill this critical gap in our knowledge by identifying new enzyme-substrate
relationships and providing new insights into how the enzymes of the system are regulated. It will apply
modern quantitative proteomic methods to identify proteins that are modified by ubiquitin, and how these
modifications change during cell division. This study will systematically examine the ability of deubiquitylating
enzymes (DUBs) to remove ubiquitin from substrates, identifying new functional roles for these enzymes. The
study will also examine the substrate specificity and regulation of specific ubiquitin conjugating enzymes and
ubiquitin ligases, the proteins that conjugate ubiquitin to other proteins. Together, the experiments outlined in
this study will identify new enzyme-substrate relationships in the UPS and provide new insights into how the
UPS controls cell division. By defining these important regulatory pathways, the findings will provide a
framework for understanding how these pathways are altered in cancer and may provide new targets for the
development of drugs to treat disease.

## Key facts

- **NIH application ID:** 11096407
- **Project number:** 3R35GM127032-07S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** RANDALL W KING
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $64,373
- **Award type:** 3
- **Project period:** 2018-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11096407

## Citation

> US National Institutes of Health, RePORTER application 11096407, Mechanistic Analysis of the Ubiquitin-Proteasome System (3R35GM127032-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11096407. Licensed CC0.

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