Normal & Disease-Associated RNA Metabolism
Nonsense-mediated mRNA decay, human disease and disease therapeutics
Research in the Maquat lab utilizes biochemistry, molecular biology, structural biology, genome editing, transcriptomics (e.g. RNA-seq, RIP-Seq, RIP-seq footprinting, NMD-Seq, TRIC-Seq), proteomics and computational biology to study RNA metabolism in human and mouse cells, as well as in the mouse, with a focus on RNA metabolism in human health and disease. As a post-doc, Dr. Maquat was the first to demonstrate that a human disease could be due to pre-mRNA splicing defects, and she also discovered mammalian-cell nonsense-mediated mRNA decay (NMD).
The Maquat lab went on to reveal that NMD, which is a type of mRNA quality control, surveys all newly synthesized mRNAs during what the lab named a "pioneer" round of translation. This round of translation involves mRNA that is associated with the cap-binding protein heterodimer CBP80 and CBP20 [Figure 1]. It is distinct from the type of translation that supports the bulk of cellular protein synthesis and that involves a different cap-binding protein, eukaryotic translation initiation factor (eIF)4E. The Maquat lab defined the “50-55-nucleotide rule”: generally, if translation terminates more than 50-55 nucleotides upstream of an exon-exon junction that is marked by what the lab called a splicing-dependent “mark”, later called an exon-exon junction complex (EJC), then the mRNA will be subject to NMD. By the time CBP80 and CBP20 have been replaced by eIF4E, the EJC “mark” has been removed so that the mRNA is largely immune to NMD diseases are nonsense-generated.
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