An HIV Feedback Resistor Auto-Regulatory Circuit Deactivator and Noise Buffer 英文参考文献.docVIP

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An HIV Feedback Resistor Auto-Regulatory Circuit Deactivator and Noise Buffer 英文参考文献.doc

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An HIV Feedback Resistor Auto-Regulatory Circuit Deactivator and Noise Buffer 英文参考文献

o PL SBIOLOGY AnHIVFeedbackResistor:Auto-Regulatory CircuitDeactivatorandNoiseBuffer Leor S.Weinberger*,Thomas Shenk DepartmentofMolecularBiology,PrincetonUniversity,Princeton,NewJersey,UnitedStatesofAmerica Animal viruses (e.g., lentiviruses and herpesviruses) use transcriptional positive feedback (i.e., transactivation) to regulatetheirgeneexpression.Butpositive-feedbackcircuitsareinherentlyunstablewhenturnedoff,whichpresents a particular dilemma for latent viruses that lack transcriptional repressor motifs. Here we show that a dissipative feedbackresistor,composedofenzymaticinterconversionofthetransactivator,convertstransactivationcircuitsinto excitablesystemsthatgeneratetransientpulsesofexpression,whichdecaytozero.WeuseHIV-1asamodelsystem and analyze single-cell expression kinetics to explore whether the HIV-1 transactivator of transcription (Tat) uses a resistortoshutofftransactivation.TheTatfeedbackcircuitwasfoundtolackbi-stabilityandTatself-cooperativitybut exhibited a pulse of activity upon transactivation, all in agreement with the feedback resistor model. Guided by a mathematicalmodel,biochemicalandgeneticperturbationofthesuspectedTatfeedbackresistoralteredthecircuit’s stability and reduced susceptibility to molecular noise, in agreement with model predictions. We propose that the feedback resistor is a necessary, but possibly not sufficient, condition for turning off noisy transactivation circuits lackingarepressormotif(e.g.,HIV-1Tat).Feedbackresistorsmaybeaparadigmforexaminingotherauto-regulatory circuitsandmayinformuponhowvirallatencyisestablished,maintained,andbroken. Citation:WeinbergerLS,ShenkT(2007)AnHIVfeedbackresistor:Auto-regulatorycircuitdeactivatorandnoisebuffer.PLoSBiol5(1):e9.doi:10.1371/journal.pbio.0050009 oligomerization of k repressor, is critical to the function of the circuit. When the repressor is abundant, it forms Introduction Many viruses encode strong transcriptional positive-feed- back(i.e.,excitatory-feedback)loopsinordertoq