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Research Interests

All RNA viruses encode a polymerase that catalyzes both replication and transcription of the viral genome. For many RNA viruses, replication and transcription are two distinct processes with different initiation and termination mechanisms. Furthermore, the rates of mRNA and viral genomic RNA synthesis often peak at different times during infection. Our laboratory is interested in the catalytic mechanisms of viral RNA polymerases and in how RNA viruses exert regulation over RNA synthesis through polymerase interactions with viral and cellular factors.

Our research currently focuses on the following two virus systems:

(a) Birnaviruses (dsRNA). Birnaviruses are pathogens of economically important animals such as chicken and fish. Viral RNA synthesis by birnavirus is initiated by the viral protein VP1, which also functions as the catalytic polymerase subunit. The VP1 crystal structure, which was recently determined in our laboratory, reveals an unusual polymerase active site topology and a novel protein-priming domain. Further functional studies combined with structural analysis of the VP1:substrate complexes will likely provide important insights into the molecular mechanism of viral protein priming.

   

(Left) The polymerase from the infectious bursal disease virus. (Right) The influenza A virus nucleoprotein.

(b) Influenza viruses (-ssRNA). Initiation of influenza viral mRNA synthesis requires a short, capped RNA primer snatched from host mRNAs. As transcription progresses toward the end of template, viral polymerase stutters at a poly(U) sequence to produce a poly(A) tail. In contrast to transcription, replication is primer-independent and the polymerase is able to read through the pre-termination signal. Replication and transcription of influenza viral RNA require four viral proteins: PA, PB1, PB2, and NP. Our laboratory uses biochemical assays and structural methods to determine how these four proteins mediate the two RNA synthesis reactions with different initiation and termination mechanisms.