# Regulation and Function of SUMO Protein Modification

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $376,117

## Abstract

PROJECT SUMMARY
Small ubiquitin related modifiers (SUMOs) function as posttranslational protein modifications and thereby
regulate nearly all essential cell functions. As such, sumoylation is linked to a variety of human diseases,
including cancer and neurodegenerative disorders, and there is great interest in targeting the SUMO pathway
for therapeutic purposes. Notably, the first phase I clinical trial of a SUMO inhibitor was recently approved for
cancer therapy. A more detailed understanding of basic molecular mechanisms regulating sumoylation and its
consequences on cell function, however, is needed to achieve the full potential of these efforts. In particular,
an ability to target specific branches of the SUMO pathway could allow for more precise therapies. Vertebrates
express multiple SUMO paralogs which could allow for such precision targeting. However, the unique
properties and functions of SUMO paralogs remain poorly understood. To address this gap in knowledge, we
are taking advantage of recently developed SUMO1 and SUMO2 knockout cell lines to define and characterize
the specific functions and molecular mechanisms of action of these two paralogs. Aims of our proposal
include: (1) We will obtain support for the hypothesis that SUMO1 and SUMO2 function as unique signals
specifying unique fates upon conjugation to proteins. This will be achieved through detailed characterization of
paralog-specific phenotypes identified in SUMO1 and SUMO2 knockout cell lines, including changes in cell
morphology, defects in proteostasis and hypersensitivities to cell stress. (2) We will test multiple hypotheses to
reveal the molecular basis for non-redundant functions of SUMO1 and SUMO2. Hypotheses concerning the
function of chain formation and selective non-covalent interactions with effector proteins will be explored
through rescue of knockout cell phenotypes using a panel of SUMO1 and SUMO2 mutant proteins. (3) We will
use proteomic and transcriptomic studies to connect the non-redundant functions of SUMO1 and SUMO2 to
paralog-specific changes in gene expression, target protein modification and association with interacting
effector proteins. Results from our studies will provide unequivocal evidence for SUMO1 an SUMO2 paralog-
specific functions and vital insights required to target specific branches of the SUMO pathway for therapeutic
purposes.

## Key facts

- **NIH application ID:** 10242207
- **Project number:** 5R01GM060980-19
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MICHAEL J. MATUNIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,117
- **Award type:** 5
- **Project period:** 2000-03-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242207

## Citation

> US National Institutes of Health, RePORTER application 10242207, Regulation and Function of SUMO Protein Modification (5R01GM060980-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242207. Licensed CC0.

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