# Mechanisms of posttranscriptional regulation of SAM homeostasis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $389,848

## Abstract

PROJECT SUMMARY/ABSTRACT
S-adenosylmethionine (SAM) is the methyl donor for nearly all cellular methylation reactions. Given the
importance of methylation in the activities of nucleic acids, proteins, and lipids, proper control of SAM is
fundamental to a wide array all of cellular processes. Nonetheless, the mechanisms cells use to maintain SAM
homeostasis remains incompletely understood. Recent data suggest a model in which a posttranscriptional
feedback loop regulates SAM levels. The model proposes that cells respond to intracellular SAM levels by
controlling intron retention of MAT2A, the RNA that encodes the major SAM synthetase. A conserved hairpin,
called hp1, in the MAT2A 3´ UTR is a key cis-acting determinant in the response and the recently
characterized RNA methyltransferase METTL16 is also central to the pathway. Under high SAM levels,
METTL16 methylates MAT2A hp1 favoring intron retention and nuclear degradation of the MAT2A transcript.
Upon SAM depletion, METTL16 binds hp1 but stays bound, presumably due to poor enzymatic turnover in low
SAM. When bound to the RNA, METTL16 functions as a splicing enhancer to promote MAT2A mRNA
production thereby increasing SAM synthetase and SAM levels. Despite significant empirical support for this
model, it only begins to define the mechanisms and biological significance of METTL16 and posttranscriptional
regulation of SAM homeostasis. The three aims in this proposal seek to further understand the biological roles
of METTL16 controlling SAM homeostasis and RNA processing. In Aim 1, the cis- and trans-acting factors
required for splicing will be defined to elucidate the mechanism of METTL16-induced splicing. In Aim 2, the
proposed links between SAM homeostasis and MAT2A regulation by METTL16 are tested. Finally, in Aim 3, an
unbiased screen is described that has identified potential new regulators of the SAM homeostasis in cells.
Because SAM is central to many cellular functions, loss of precise control of SAM levels has potentially serious
consequences for human health. The work described here will define mechanisms cells use to maintain SAM
homeostasis.

## Key facts

- **NIH application ID:** 10077306
- **Project number:** 5R01GM127311-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** NICHOLAS K CONRAD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,848
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077306

## Citation

> US National Institutes of Health, RePORTER application 10077306, Mechanisms of posttranscriptional regulation of SAM homeostasis (5R01GM127311-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10077306. Licensed CC0.

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