mRNA 3′UTRs chaperone intrinsically disordered regions to control protein activity
Memorial Sloan Kettering Cancer Center, New York, USA
@CECAD, Lecture Hall (ground floor)
Host: Dr. Débora Broch Trentini Schmidt, CMMC, University of Cologne
ABSTRACT
More than 2,700 human mRNA 3′UTRs have hundreds of highly conserved (HC) nucleotides, but their biological roles are unclear. Here, we show that mRNAs with HC 3′UTRs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. These proteins are only fully active when translated from mRNA templates that include their 3′UTRs, raising the possibility of functional interactions between 3′UTRs and IDRs. Rather than affecting protein abundance or localization, we find that HC 3′UTRs control transcriptional or histone demethylase activity through co-translationally determined protein oligomerization states that are kinetically stable. 3′UTR-dependent changes in protein folding require mRNA-IDR interactions, suggesting that mRNAs act as IDR chaperones. These mRNAs are multivalent, a biophysical RNA feature that enables their translation in network-like condensates, which provide favorable folding environments for proteins with long IDRs. These data indicate that the coding sequence is insufficient for the biogenesis of biologically active conformations of IDR-containing proteins and that RNA can catalyze protein folding.
ABOUT DR. MAYR
Dr. Christine Mayr, MD, PhD is a Full Member of the Sloan Kettering Institute and Professor at the Gerstner Sloan Kettering Graduate School of Biomedical Sciences and Weill Cornell Medical College. She received her M.D. from Free University Berlin and earned her Ph.D. in Immunology, magna cum laude, from Humboldt University in Berlin. Her early research training included graduate work at Charité and the Free University, followed by clinical residencies and postdoctoral fellowships in Munich, Germany. She later joined the laboratory of David Bartel at the Whitehead Institute/MIT, where she focused on RNA biology. In 2009, Dr. Mayr established her independent laboratory at Memorial Sloan Kettering Cancer Center in the Cancer Biology and Genetics Program. Her groundbreaking work on mRNA 3′ untranslated regions (3′UTRs) has reshaped our understanding of post-transcriptional gene regulation. Her research was recognized as a scientific breakthrough by Science Signaling in 2013, and she received the NIH Director’s Pioneer Award in 2016 for her innovative contributions to molecular biology. Dr. Mayr has held multiple academic appointments, including professorships in Biochemistry, Molecular Biology, and Computational Biology and Medicine. She has been honored with numerous awards, such as the Pershing Square Sohn Prize for Young Investigators in Cancer Research, the Damon Runyon-Rachleff Innovation Award, and the Louise and Allston Boyer Young Investigator Award. In addition to her research, she plays an active role in the scientific community through editorial board service, grant review panels, and international conference organization.