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An endogenous accelerator for viral gene expression confers a fitness advantage

Author(s): Teng, Melissa W; Bolovan-Fritts, Cynthia; Dar, Roy D; Womack, Andrew; Simpson, Michael L; et al

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Abstract: Many signaling circuits face a fundamental tradeoff between accelerating their response speed while maintaining final levels below a cytotoxic threshold. Here, we describe a transcriptional circuitry that dynamically converts signaling inputs into faster rates without amplifying final equilibrium levels. Using time-lapse microscopy, we find that transcriptional activators accelerate human cytomegalovirus (CMV) gene expression in single cells without amplifying steady-state expression levels, and this acceleration generates a significant replication advantage. We map the accelerator to a highly self-cooperative transcriptional negative-feedback loop (Hill coefficient ∼7) generated by homomultimerization of the virus's essential transactivator protein IE2 at nuclear PML bodies. Eliminating the IE2-accelerator circuit reduces transcriptional strength through mislocalization of incoming viral genomes away from PML bodies and carries a heavy fitness cost. In general, accelerators may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules.
Publication Date: 21-Dec-2012
Citation: Teng, Melissa W, Bolovan-Fritts, Cynthia, Dar, Roy D, Womack, Andrew, Simpson, Michael L, Shenk, Thomas, Weinberger, Leor S. (2012). An endogenous accelerator for viral gene expression confers a fitness advantage. Cell, 151 (7), 1569 - 1580. doi:10.1016/j.cell.2012.11.051
DOI: doi:10.1016/j.cell.2012.11.051
ISSN: 0092-8674
EISSN: 1097-4172
Pages: 1569 - 1580
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Cell
Version: Author's manuscript

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