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SUMMARY:From Screens to Genes: Unraveling the Mystery of Poxvirus Genome U
 ncoating - Jason Mercer\, Institute of Biochemistry\, ETH Zürich\, Switze
 rland
DTSTART:20130718T130000Z
DTEND:20130718T140000Z
UID:TALK46228@talks.cam.ac.uk
CONTACT:Dr Tennie Videler
DESCRIPTION:The main goal of all viruses is to deliver a replication-compe
 tent genome from one cell or organism to another. Thus\, the uncoating of 
 viral genomes from incoming capsids is a critical step in the lifecycle of
  all viruses. Genome delivery is an active process for which different mec
 hanisms exist depending on the virus itself and the cellular location of r
 elease.\nPoxviruses\, including the causative agent of smallpox and vaccin
 ia virus (VACV) the smallpox vaccine\, uncoat and replicate their genome i
 n the cytoplasm. Interestingly\, the poxviruses are the only mammalian vir
 uses known to require both cellular and viral factors to mediate genome un
 coating. For nearly 40 years the mechanisms and factors required for this 
 process have remained a mystery.  \n	Since its discovery\, RNA interferenc
 e (RNAi) has been the method of choice for large-scale loss-of-function st
 udies. Using parallel automated\, high-throughput RNAi silencing screens w
 e set out to identify host cell factors required for VACV infection and vi
 ral factors needed for genome uncoating. For cell factors: 7\,000 genes we
 re screened revealing a new mechanism for genome uncoating involving the u
 biquitination of viral core proteins during virus assembly and subsequent 
 released of the viral DNA from the core through the activity of the cell
 ’s proteasomes.  For viral factors: the first large-scale RNAi screen di
 rected against a single virus was generated. Targeting of 80 conserved VAC
 V genes led to the unambiguous identification of the VACV AAA+ ATPase D5 a
 s the poxvirus-uncoating factor. RNAi-mediated down-regulation of D5 in vi
 vo resulted in reduced viral replication and spread\, highlighting the pot
 ential of such libraries to provide simultaneous identification of antivir
 al targets and complementary therapeutics.\nThe results accentuate the val
 ue of large-scale RNAi screens in providing directions for detailed cell b
 iological investigation of complex pathways\, investigation of large DNA v
 irus gene function\, and identification of effective antiviral RNAs. \n
LOCATION:MPLT\, MRC-LMB\, Francis Crick Avenue\, Cambridge Biomedical Camp
 us\, CB2 0QH
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