17 - adeno - notes II.docx

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University of Toronto St. George
Molecular Genetics and Microbiology
Alan Cochrane

VIRION CORE CONTAINS Adenovirus – linear dsDNA genome – inverted terminal repeats at ends – five prime end – covalently linked protein called terminal protein – Early proteins scattered over genome – some transcribed on one strand, tend to have own promoters – each of early genes can be spliced different ways – E1A proteins are a group, related but different Late proteins all come from common promoter – also have splicing to get single messenger RNA spliced, tripartite leader sequence Goals of early gene expression 1. Induce host cell to enter S phase – virus cannot do anything – able to manipulate cell to enter S phase a. Combination of proteins E1A and E1B, and E4 2. Set up systems to protect infected cell from antiviral defences of host – host cell can detect if it’s infected with virus – limit spread of virus, undergo apoptosis – counteracting normal defense mechanisms of cell – virus tends to be one step ahead of cell a. Bunch of proteins in adenovirus contributing to this – stable RNA molecule called BA RNA 3. Make viral proteins needed for DNA replication – a. E1A protein – two expressed early – three more expressed later in infection E1A – works by binding two specific cellular proteins – one of which is PRB (retinoblastoma protein) – normally this protein controls expression or negatively regulates expression of genes that promote S phase progression – transcription factor called E2F, a cellular protein – normally activates expression of genes important for S phase, like DNA replication proteins – RB combine to this, and represses function of E2F – turn off expression of cell cycle genes – binding of RB to E2F regulated through phosphorylation – cell can turn or off – Part of RB works in suppressing gene expression is by recruiting H-daC – histone D acetylase – acetylation of histones or histone tails determines whether chromatin active and can be transcribed or not – E1A – can efficiently bind to RB – same place that E2F binds – blocks RB binding – in presence of E1A – whereh E2F active and turns on genes promoting S phase progression E1A can recruit PRB to promoters of antiviral genes – not clear how but involve turning them off – brings suppressor proteins to antiviral genes while turning off Another interaction E1A makes is with histone acetyl transferases – opposite of DAC - P300 and cBP - Histone octomer shown with DNA wrapped around it – tails at N terminus modified by various things – when in non-acetylated state – more associated with DNA, tight coplex and most proteins cannot access DNA when wrapped this way – - HAT – changes structure so less associated with DNA – E1A can activate expression of several genes by binding to proteins and brining them to particular sites – can turn on certain cell cycle genes by recruiting the proteins and in doing this, b/c binds efficiently to these proteins – can affect histone aceylation – can have decreased histone aceylation to prooters not associated with E1A E1A also binds to TAT binding roteins – general transcription factors that sit on TATA boxes Virus also uses TATA sites in promoter – one of the important role of E1A – recruited to viral promoters and turn on early gene expression Also E1A can interact with specific transcription factors – E1B function – interaction with p53, a cellular protein that is transcription factor that binds to specific sequences upstream of certain genes, and controls genes negatively regulates cell cycle progression - P53 normally turn on things that block cell cycle - Turn off cell cycle inhibitors – opposite of what E1A is doing but end result is the same - Mechanisms o Block transcriptional activation by P53 o Can work in complex with E4 – when combined, make E3 ubiquitin ligase  Can transfer ubiquitin to _____________  By promoting ubiquitnation – decrease total cellular levels of p53 – o P53 tends to build up in cells in response to various things – triggers apoptosis as well  Viruses want p53 levels to be low o Part of indirect effects of e1a – higher levels of p53 – if do nt have e1b, cells would just die - Another form of E1b protein mimicks cellular Bcl2 protein and inhibits apoptosis through association with mitochondrial membranes E3 function known to affect expression of cell surface receptors and inhibit secretion of pro inflammatory molecules – immune cells alerted to virus – E3 disrupting this process, so infected cells not destroyed by immune system E4 – cause reorganization of PML nuclear bodies – also called nuclear domains - Nucleus of cells – form little docking stations in nucleus where other proteins can associate – controlling important processes in mammals – like apoptosis – - PML usually suppresses lytic viral infectio - Viruses encode proteins that muck with PML bodies – so do not function properly – by inducing degradation of PML proteins, but adnoviruses do not do this, they reorganize into track like structures o Once reorganized, do not function properly – PML bodies - E4
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