Papillomaviruses_MGY378_2014

Papillomaviruses_MGY378_2014 - 2008 Nobel Prize in Medicine...

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2008 Nobel Prize in Medicine 2008 Nobel Prize in Medicine Harald zur Hausen Harald zur Hausen "for his discovery of human papilloma viruses causing cervical cancer"
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Papillomaviruses Numerous viruses that infect mammals and some birds Approximately 200 different human viruses identified Virions look like polyomaviruses but slightly bigger (55 nM diameter) Genome is circular dsDNA, 8,000 bp long (complexed with histones) Most papillomaviruses infect squamous epithelial cells, causing benign epithelial tumours (called papillomas or warts) eg. all human viruses (HPVs) A small group of papillomaviruses infect dermal fibroblasts causing benign fibroepithelial tumours (fibropapillomas) eg. bovine papillomavirus (BPV)
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HPV Infection of Epithelium virions released synthesis of capsid proteins, virion assembly amplification of viral DNA early gene expression plasmid DNA replication infection of stem cells corneal layer granular layer spinous layers basal layer differentiation Stages of infection of squamous epithelial cells is tightly linked to the differentiation stage of the cells. Initial infection can only occur in cells capable of dividing (basal cells).
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Genome Organization Genome forms nucleosomes with cellular histones as for polyomavirus Organized into early and late regions separated by regulatory sequences called LCR (long control region) or URR (upstream regulatory region) All genes transcribed from 1 DNA strand (same direction around genome) 1 early promoter in HPV; several in BPV Final mRNA generated by alternative splicing
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Early Gene Expression Early genes can only be expressed in certain cell types due to requirement for cellular factors that bind LCR enhancer elements Early genes: E1 – required for DNA replication E2 – roles in transcription, DNA replication, viral DNA segregation E3 – function unknown (not in HPV) E5, E6, E7 – roles in cellular transformation E8- small protein interaction domain that can be fused to E2; represses transcriptional activation by E2
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Transcription Regulation by E2 LCR contains an enhancer that is activated by E2 E2 activates the expression of all early genes by binding the enhancer E2 contains separate DNA binding and activation domains Transcription activation involves E2 recruiting cellular Brd4 protein to enhancer (E2 binds Brd4 through activation domain) Truncated forms of E2 are also produced that bind DNA but lack the transactivation domain (in some cases fused to E8). These inhibit activation by full length E2 by competing for DNA binding sites. This results in down regulation of early gene expression Full length E2 Truncated E2
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Late Gene Expression Occurs only in differentiated keratinocytes for HPV Late proteins are L1, L2 and E4 Transcribed from 1 promoter (P L ) that is activated in differentiated cells of the wart L1 and L2 – capsid proteins E4 – in early region of genome but expressed late in infection - plays role in viral egress by disrupting keratin cytoskeleton
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  • Spring '14
  • DNA, high risk, Human papillomavirus

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