# Methyltransferase Contributions to Genomic Stability and Cancer

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $432,911

## Abstract

ABSTRACT
Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer
phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to
many traditional therapies. One recent discovery in this cancer is high frequency mutation of SETD2, a histone
methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 (H3K36me3)
trimethylation mark on actively transcribed genes. Our two groups have in parallel made a series of very
exciting discoveries related to a new role for the SETD2 methyltransferase as a tumor suppressor
required for genomic stability. First, we observed that loss of the H3K36me3 mark on chromatin impairs
repair of DNA double strand breaks. This suggests that loss of SETD2 causes a DNA repair defect, which we
hypothesize is due to mis-directed H3K36me3 “readers” that would normally guide DNA repair machinery to
double strand breaks, resulting in genomic instability. Independently, we recently made the exciting discovery
of an important novel nonhistone target for the SETD2 methyltransferase: microtubules. These data show that
SETD2 methylation of α-tubulin on lysine 40 (K40Me) of mitotic microtubules is required for proper
chromosome segregation and cytokinesis, opening the door for understanding how loss of SETD2 contributes
to genomic instability and progression of RCC in a completely new way. We are proposing a multifaceted
collaborative project to understand 1) how SETD2 function as a histone and microtubule methyltransferase
contributes to genomic stability, and the development of RCC 2) the mechanism linking histone methylation
deficits to DNA double strand break repair deficiency, and 3) exploit what we know of this enzyme and the
biology of disruption to identify pharmacologic tool compounds, which we will test in vivo for exploring key
biological properties of genome maintenance or which hold promise for future targeted therapeutics.

## Key facts

- **NIH application ID:** 9935000
- **Project number:** 5R01CA203012-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** WENDY KIMRYN RATHMELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,911
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935000

## Citation

> US National Institutes of Health, RePORTER application 9935000, Methyltransferase Contributions to Genomic Stability and Cancer (5R01CA203012-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9935000. Licensed CC0.

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