# The SMYD lysine methyltransferase Set6 in signaling and proteostasis

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE COUNTY · 2020 · $180,769

## Abstract

PROJECT SUMMARY
Protein homeostasis, or proteostasis, is achieved through a regulated network of the translational
machinery, molecular chaperones, and protein degradation factors, which function to maintain the
abundance of the cell’s proteins in folded, soluble, non-aggregated states. Deterioration of the
proteostasis network is a hallmark of aging cells and underlies numerous diseases associated
with aging. A key mechanism regulating factors within the proteostasis network is their post-
translational modification, including methylation at lysine residues. The SMYD family of lysine
methyltransferases has been shown to interact with molecular chaperones in diverse systems,
and there are numerous reported lysine methylation sites on factors that contribute to
proteostasis. However, our knowledge of the methyl-lysine substrates targeted by SMYD
methyltransferases and their functional interactions with the proteostasis network is still very
limited. The primary objective of the proposed work is to leverage proteomic and molecular tools
in the model system Saccharomyces cereviasie to define the substrates for the yeast SMYD
enzyme Set6, a largely uncharacterized protein, and determine its molecular function in regulating
the proteostasis network. In Aim I, we will use high-resolution mass spectrometry to identify
targets of Set6 proteome-wide and perform molecular and biochemical characterization of lysine
methylation on the newly-identified substrates. In Aim II, we will use molecular and genetic tools
to define the role of Set6 in interacting with and regulating the proteostasis network to prevent the
accumulation of unfolded proteins. In total, this work will integrate proteomic and genetic analyses
to advance our understanding of the mechanistic links between the SMYD family lysine
methyltransferases and molecular chaperones. We expect this work to provide new insights into
regulatory mechanisms critical to proteostasis, which may shed light on new targets for
therapeutic interventions into diseases associated with protein misfolding and aggregation.
Furthermore, these studies will also develop a well-characterized, genetic model system for
dissecting the molecular mechanisms by which SMYD enzymes contribute to proteostasis and
determining how their manipulation may prevent aging-associated pathologies.

## Key facts

- **NIH application ID:** 9976423
- **Project number:** 5R21AG064507-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE COUNTY
- **Principal Investigator:** Erin Green
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $180,769
- **Award type:** 5
- **Project period:** 2019-07-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976423

## Citation

> US National Institutes of Health, RePORTER application 9976423, The SMYD lysine methyltransferase Set6 in signaling and proteostasis (5R21AG064507-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976423. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*