Biology Seminar Series - Alice Telesnitsky, University of Michigan

HIV-1 uses a single promoter to transcribe all mRNAs needed to express its fifteen proteins and its genomic RNAs. A longstanding question in retrovirology has been how these functionally distinct RNAs are specified from a single transcription unit. Performing collaborative work with structural biologists provided evidence that alternate folds of viral 5' end sequences specified whether an RNA would serve as genome or as mRNA. Our initial assumption was that RNAs were directed into one fate pathway or another because the RNAs isomerized between alternate structures that were subsequently locked in place by protein binding. However, while studying these processes in infected cells, we made the surprising discovery that alternate RNA folds are instead dictated by micro-heterogeneity at RNA 5' ends. Specifically, HIV-1 transcription initiates at two sites separated by two base pairs, generating two RNA 5' end isoforms: one that initiates with three guanosines (3G RNA) and adopts a fold incompatible with RNA dimerization, and second transcript form with a single 5' guanosine (1G RNA) that adopts the dimeric form required for genome packaging. In ongoing work, we are examining how 1G and 3G RNAs differentially potentiate alternate RNA folds, how these folds dictate alternate roles in viral replication, and how 1G and 3G RNAs differ in their interactions with host RNA sensing machinery: resulting in dramatic effects on host innate immune signaling.

Alice Telesnitsky was born and raised in Los Angeles (5th generation Californian except one grandfather born in Allendale, MI in the 19th century) and was educated kindergarten through PhD in the California public schools. After receiving her PhD in Biochemistry at Berkeley (bacterial polymerase mechanisms, Mike Chamberlin lab), she performed postdoctoral work on retroviral reverse transcriptase with Steve Goff at Columbia University in NYC. She moved to Ann Arbor 30 years ago and has been a faculty member in Microbiology and Immunology at the University of Michigan ever since.