Nonsense-Mediated mRNA Decay in Human Health and Disease: Reframing the Role of FMRP in Fragile X Syndrome

This Translational Science Grand Rounds presentation will focus on understanding the importance of nonsense-mediated mRNA decay (NMD) to normal and disease-associated mRNA metabolism, predicting which mutations in an mRNA will trigger NMD, and appreciating the complicated web of co- and post-transcriptional gene control. NMD is always "on" in all of our cells, although with different efficiencies. While we initially discovered NMD through RNA-centric studies of inherited hemolytic anemias, we now know that NMD eliminates one-third of mRNAs that we routinely make by mistake, and NMD efficiency is altered by cells as a means to adapt to various stressors. Mechanistic aspects of NMD will be overviewed before transitioning to how our continued studies of NMD serendipitously led us to elucidate RNA metabolic abnormalities in Fragile X Syndrome. Presented by Lynne E. Maquat, PhD, J. Lowell Orbison Endowed Professor, Department of Biochemistry and Biophysics, Oncology, and Pediatrics, University of Rochester Medicine. This Translational Science Grand Rounds event is sponsored and organized by the Clinical and Translational Science Institute. Lynne E. Maquat, PhD, is the J. Lowell Orbison Endowed Chair and Professor of Biochemistry & Biophysics who holds concomitant appointments in Pediatrics and in Oncology, Founding Director of the Center for RNA Biology, and Founding Chair of Graduates Working in Science at the University of Rochester. After obtaining her PhD in Biochemistry from the University of Wisconsin-Madison and undertaking post-doctoral work at the McArdle Laboratory for Cancer Research, she joined Roswell Park Cancer Institute before moving to the University of Rochester Medical Center. Dr. Maquat’s research focuses on the molecular basis of human diseases, with particular interest in mechanisms of mRNA decay. Maquat discovered nonsense-mediated mRNA decay (NMD) in human diseases in 1981 and, subsequently, the exon-junction complex (EJC) and how the EJC marks mRNAs for a quality-control “pioneer” round of protein synthesis. She also discovered Staufen-mediated mRNA decay, which mechanistically competes with NMD and, by so doing, new roles for short interspersed elements and long non-coding RNAs. Additionally, she defined a new mechanism by which microRNAs are degraded, thereby regulating mRNAs so as to promote the cell cycle. One of her current interests focuses on the development of therapeutics for diseases that she has shown manifest hyperactivated NMD, including the most common single gene cause of intellectual disability and autism, Fragile X Syndrome. Maquat is an elected Fellow of the American Association for the Advancement of Science (2006); an elected Member of the American Academy of Arts & Sciences (2006), the National Academy of Sciences (2011), and the National Academy of Medicine (2017); and a Batsheva de Rothschild Fellow of the Israel Academy of Sciences & Humanities (2012-3). She was recently elected to the Council of Scientific Advisors for the International Centre for Genetic Engineering and Biotechnology (ICGEB), an initiative of the United Nations Industrial Development Organization (2022). She received the William C. Rose Award from the American Society for Biochemistry & Molecular Biology (2014), a Canada Gairdner International Award (2015), the international RNA Society Lifetime Achievement Award in Service (2010) and in Science (2017), the FASEB Excellence in Science Award (2018), the Vanderbilt Prize in Biomedical Science (2017), the Wiley Prize in Biomedical Sciences from Rockefeller University (2018), the International Union of Biochemistry and Molecular Biology Medal (2019), the Wolf Prize in Medicine from Isreal (2021), the Warren Alpert Foundation Prize from Harvard Medical School (2021), and the Gruber Genetics Prize from the Gruber Foundation and Yale University (2023). Most recently, she has been awarded the Dr. Paul Janssen Prize in Biomedical Research from Johnson & Johnson (2024), and the Albany Prize in Medicine and Biomedical Research from Albany Medical Center (2024), and she will be receiving the Indiana University School of Medicine Steven C. Beering Award (2026). Maquat is also well-known for her national and international efforts to promote women in science. Accreditation The University of Rochester School of Medicine and Dentistry is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Certification The University of Rochester School of Medicine and Dentistry designates this live activity for a maximum of 1.00 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.