# Role of sumoylation in aging

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2020 · $154,000

## Abstract

Project Summary/Abstract:
The mechanisms that maintain proper function and folding of the proteome (proteostasis) decline during normal
aging, which facilitates the onset and progression of neurodegenerative protein misfolding diseases, including
Alzheimer's Disease. The functional integrity of the proteome is safeguarded from stress through the combined
action of a cohort of transcription factors, each primed to respond to specific forms of proteotoxic stress. During
aging, these responses decline and ultimately precipitate a collapse of proteostasis. C. elegans is an excellent
model to study the molecular mechanisms involved in this complex process: in particular, the inducibility of the
heat shock response, mitochondrial unfolded protein response, ER unfolded protein response, and the oxidative
stress response all rapidly decline concurrent with early signs of declining proteostasis. Why the inducibility in
response to diverse forms of proteotoxic stress declines, however, is poorly understood, but coincides with the
formation of repressive chromatin marks at stress loci. We have identified inappropriate sumoylation during aging
as a potential mechanism to explain loss of stress response inducibility. This project will explore how changes
in sumoylation during aging alter the epigenome, inducibility of stress responses, and maintenance of
proteostasis. The objectives of this proposal are to identify nuclear changes in sumoylation during aging and
gain mechanistic insight into how altered sumoylation intersects with changes in chromatin, inducibility of stress
response, and the consequence on proteostasis and longevity. Our central hypothesis is that the inducibility of
stress response programs maintaining proteostasis declines because increased sumoylation results in aberrant
recruitment of chromatin remodeling complexes to stress loci. We have discovered an age-associated increase
in sumoylation of a transcriptional regulator of proteostasis, and blocking sumoylation prevents the
downregulation of stress response in adult animals. Conversely, preventing deSUMOylation shortens lifespan
and represses gene expression. Notably, expression can be rescued by inactivation of chromatin modifying
enzymes, consistent with the notion that age-related changes in sumoylation are linked to the activity of
chromatin remodeling complexes. Aim 1 is centered on deciphering whether increasing sumoylation during early
C. elegans aging, which coincides with the precipitous drop in stress response, is causative in declining
proteostasis and longevity. Aim 2 centers on a mechanistic analysis to identify interconnections between
sumoylation, chromatin remodeling complexes, and changes in chromatin at stress loci. The focus of Aim 3 is
on the transcription factors themselves that directly regulate components of the proteostatic network and the
functional consequence of their sumoylation during aging. Many of the causative factors of neurodegenerative
diseases are sum...

## Key facts

- **NIH application ID:** 9981595
- **Project number:** 5R21AG064519-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Andrew Vaughn Samuelson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $154,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981595

## Citation

> US National Institutes of Health, RePORTER application 9981595, Role of sumoylation in aging (5R21AG064519-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9981595. Licensed CC0.

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