Dr. Nicholas Conrad and graduate student Kathryn Pendleton

DALLAS – May 2017 – UT Southwestern Medical Center researchers have identified a feedback loop that precisely maintains levels of a metabolite essential for many cellular processes. Their basic science findings could have implications for many diseases, including cancer.

“Many processes in the cell are regulated by methylation, in which enzymes called methyltransferases transfer a methyl group from the donor metabolite S-adenosylmethionine (SAM) to biologically important molecules, such as RNA,” said Dr. Nicholas Conrad, Associate Professor of Microbiology and senior author of the study published in Cell. “Cells must maintain proper SAM levels in order to allow methyltransferases to control RNA and other molecules within the cell. Until now, just how cells sense SAM and maintain it at proper levels has been unknown. We found a clue that is essential for solving that mystery.”

The study describes a previously unknown mechanism that cells use to regulate SAM levels: a feedback loop in which a methyltransferase called METTL16 acts as the “sensor.”

It was known that the MAT2A messenger RNA (mRNA) encodes the protein used in the chemical reaction that produces SAM. The new study found that when SAM levels are high in the cell, METTL16 transfers methyl from SAM to the MAT2A RNA, which in turn slows the production of the MAT2A protein and thereby lowers the production of SAM. Conversely, when SAM levels are low in the cell, the study showed that METTL16 cannot methylate MAT2A RNA, which in turn promotes the production of more MAT2A mRNA, leading to increased production of the MAT2A protein and subsequently of the methyl donor SAM. Thus, cells use METTL16 as a “SAM-sensor” that detects low SAM levels and then promotes the expression of the protein that makes SAM, Dr. Conrad explained.

The study involved collaborations with Associate Professor of Biochemistry Dr. Benjamin Tu, whose laboratory provided key data and insights on SAM metabolism, and Dr. Yang Xie, Associate Professor of Clinical Sciences and Bioinformatics who is also Director of the Quantitative Biomedical Research Center. Lead author of the study is graduate student Kathryn Pendleton.

“Due to the importance of methylation in a wide variety of cellular processes, our work has implications for a broad range of diseases. As an example, certain cancer cells require higher SAM levels than corresponding normal cells,” Dr. Conrad said. “In principle, if we could develop drugs that interfere with this SAM-sensing system, then normal cells may tolerate decreases in SAM that will kill cancer cells. Currently, we are exploring these promising possibilities.”

Dr. Conrad is a Southwestern Medical Foundation Scholar in Biomedical Research.

Dr. Tu is a W.W. Caruth, Jr. Scholar in Biomedical Research.