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

About

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.