The RNA Lariat Debranching Enzyme Dbr1: Structure and Mechanism

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Thursday, April 26, 2018 12:00pm - 1:00pm
70 Ship Street, Room 106

Nathaniel Clark
Dept of Molecular Biophysics and Biochemistry
UT Health Science Center, San Antonio

"The RNA Lariat Debranching Enzyme Dbr1: Structure and Mechanism"

The RNA lariat debranching enzyme (Dbr1) plays an important role in RNA homeostasis in eukaryotic cells. Splicing of introns generates lariat RNA with an unusual 2’,5’-phosphodiester bond. The only enzyme known to debranch these RNA lariats is Dbr1. Some functional non-coding RNAs derive from intronic RNA, including small nucleolar RNAs that aid in ribosome assembly and approximately one third of the currently known micro RNAs. It is likely that some roles of these RNA lariats remain undiscovered. A recent paper has shown that accumulation of RNA lariats in Δdbr1 cells has a protective effect against TDP-43 toxicity in models of amyotrophic lateral sclerosis (ALS), suggesting that inhibitors of Dbr1 may benefit ALS patients. We have determined the x-ray crystal structure of Dbr1 from Entamoeba histolytica, and analyzed the effect of different metal substitutions in the active site as well as the interaction of an inactive Dbr1 variant with a bona fide branched RNA substrate. We have developed a fluorogenic Dbr1 substrate, and employed this substrate to interrogate the metal cofactors required by Dbr1 with surprising results. To have a clearer understanding of Dbr1’s role in biology and human disease, we are examining the expression and processing of Dbr1 in mouse tissue, and in tissue samples from ALS patients. These results, and a recent finding that mutations in Dbr1 predispose humans to viral encephalitis, suggest that Dbr1 has an important, yet poorly-understood role in neuronal processes.

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