Abstract: Series 113, Lecture 1

The Harvey Lectures Series 113 (2017—2018)

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Lecture #1: Thursday, October 19, 2017 — Time and Location

Nonsense-Mediated mRNA Decay and Human Disease: Genome Guardian and Executor

Lynne Maquat, PhD

Lynne Maquat, PhD

Professor, Department of Biochemistry and Biophysics
Professor, Cancer Center
Director, Center for RNA Biology

University of Rochester Medical Center

Rochester, New York

Dr Maquat's Website

Much 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 contain a premature termination codon. Our studies of NMD have led to the discovery of the pioneer round of translation, the post-splicing “mark” on newly synthesized mRNAs, the mechanistically related and competing Staufen-mediated mRNA decay pathway, including new roles for SINEs, and most recently a microRNA decay pathway. We have described the molecular mechanism for how NMD targets are discriminated from other transcripts: the central NMD factor – the ATP-dependent RNA helicase UPF1 – preferentially associates with mRNA 3′ untranslated regions (3′ UTRs) in a way that correlates with 3′ UTR length and the presence of a 3′ UTR EJC. Importantly, NMD also targets ~10% of physiologic mRNAs that are key to maintaining cellular homeostasis in a changing environmental milieu. For example, we reported that a sufficient level of DNA damage induced by commonly used frontline chemotherapeutics inhibits NMD by triggering the caspase-mediated cleavage of sub-stoichiometric amounts of UPF1, thereby upregulating the half-lives of mRNAs that include those encoding proteins promoting apoptosis. Notably, the modest inhibition of NMD promotes, but is not sufficient for, programmed cell death.