You are invited to the seminar hosted by the Institute of Molecular and Cell Biology on Nonsense-mediated mRNA Decay in Human Health and Disease, by Prof Lynne E. Maquat. Date: Tuesday, 6 June 2023Time: 11.00AM – 12.00PMHost: Prof Hong WanjinAbstractMuch progress has been made on how nonsense-mediated mRNA decay (NMD), which we first described for humans in 1981, controls the quality of gene expression by detecting and rapidly degrading aberrant mRNAs that harbor a premature termination codon. Our studies of NMD have led to the discovery of unanticipated connections between nuclear and cytoplasmic RNA metabolism, including the pioneer round of translation, and the post-splicing "mark" that is deposited on newly synthesized mRNAs, which we later named the exon-junction complex (EJC). We have also described the molecular mechanism for how NMD targets are discriminated from other cellular transcripts: the central NMD factor – the ATP-dependent RNA helicase UPF1 – preferentially associates with NMD targets by virtue of a 3’-untranslated region (UTR) EJC or a 3’ UTR sequence and/or structure. Importantly, NMD degrades the many mRNAs that we routinely make by mistakes in splicing or 3’ end formation. NMD also degrades ~5-10% physiologic mRNAs that are key to the maintenance of cellular homeostasis in a changing environmental milieu. NMD can be misregulated in diseases. I will present the mechanism by which Fragile X Syndrome (FXS) – a leading cause of intellectual disability and autism due to a deficiency in the RNA-binding protein Fragile X Protein (FMRP) – manifests global hyperactivation of NMD in FXS patient-derived cells and a mouse model of FXS. Possible therapeutic approaches will be discussed.BiographyLynne 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 Graduate Women in Science at the University of Rochester, Rochester, NY. 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. Dr. 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 has 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. Dr. 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 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 Israel (2021), the Warren Alpert Foundation Prize from Harvard Medical School (2021), and the Gruber Genetics Prize from the Gruber Foundation and Yale University (2023). Dr. Maquat is well-known for her efforts to promote women in science.
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