Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter

Adeno-associated virus serotype 2 (AAV2) can efficiently replicate in cells that have been infected with helper viruses, such as adenovirus or herpesvirus. However, in the absence of helper virus infection, AAV2 establishes latency by integrating its genome site specifically into PPP1R12C, a gene lo...

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Main Authors:	Dutheil, Nathalie, Smith, Sarah C., Agúndez, Leticia, Vincent-Mistiaen, Zoé I., Escalante, Carlos R., Linden, R. Michael, Henckaerts, Els
Format:	Online
Language:	English
Published:	American Society for Microbiology 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135950/

id	pubmed-4135950
recordtype	oai_dc
spelling	pubmed-41359502014-08-26 Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter Dutheil, Nathalie Smith, Sarah C. Agúndez, Leticia Vincent-Mistiaen, Zoé I. Escalante, Carlos R. Linden, R. Michael Henckaerts, Els Virus-Cell Interactions Adeno-associated virus serotype 2 (AAV2) can efficiently replicate in cells that have been infected with helper viruses, such as adenovirus or herpesvirus. However, in the absence of helper virus infection, AAV2 establishes latency by integrating its genome site specifically into PPP1R12C, a gene located on chromosome 19. This integration target site falls into one of the most gene-dense regions of the human genome, thus inviting the question as to whether the virus has evolved mechanisms to control this complex transcriptional environment in order to facilitate integration, maintain an apparently innocuous latency, and/or establish conditions that are conducive to the rescue of the integrated viral genome. The viral replication (Rep) proteins control and direct every known aspect of the viral life cycle and have been shown to tightly control all AAV2 promoters. In addition, a number of heterologous promoters are repressed by the AAV2 Rep proteins. Here, we demonstrate that Rep proteins efficiently repress expression from the target site PPP1R12C promoter. We find evidence that this repression employs mechanisms similar to those described for Rep-mediated AAV2 p5 promoter regulation. Furthermore, we show that the repression of the cellular target site promoter is based on two distinct mechanisms, one relying on the presence of a functional Rep binding motif within the 5′ untranslated region (UTR) of PPP1R12C, whereas the second pathway requires only an intact nucleoside triphosphate (NTP) binding site within the Rep proteins, indicating the possible reliance of this pathway on interactions of the Rep proteins with cellular proteins that mediate or regulate cellular transcription. American Society for Microbiology 2014-08 /pmc/articles/PMC4135950/ /pubmed/24829354 http://dx.doi.org/10.1128/JVI.00412-14 Text en Copyright © 2014 Dutheil et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license (http://creativecommons.org/licenses/by/3.0/) .
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Dutheil, Nathalie Smith, Sarah C. Agúndez, Leticia Vincent-Mistiaen, Zoé I. Escalante, Carlos R. Linden, R. Michael Henckaerts, Els
spellingShingle	Dutheil, Nathalie Smith, Sarah C. Agúndez, Leticia Vincent-Mistiaen, Zoé I. Escalante, Carlos R. Linden, R. Michael Henckaerts, Els Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
author_facet	Dutheil, Nathalie Smith, Sarah C. Agúndez, Leticia Vincent-Mistiaen, Zoé I. Escalante, Carlos R. Linden, R. Michael Henckaerts, Els
author_sort	Dutheil, Nathalie
title	Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
title_short	Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
title_full	Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
title_fullStr	Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
title_full_unstemmed	Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter
title_sort	adeno-associated virus rep represses the human integration site promoter by two pathways that are similar to those required for the regulation of the viral p5 promoter
description	Adeno-associated virus serotype 2 (AAV2) can efficiently replicate in cells that have been infected with helper viruses, such as adenovirus or herpesvirus. However, in the absence of helper virus infection, AAV2 establishes latency by integrating its genome site specifically into PPP1R12C, a gene located on chromosome 19. This integration target site falls into one of the most gene-dense regions of the human genome, thus inviting the question as to whether the virus has evolved mechanisms to control this complex transcriptional environment in order to facilitate integration, maintain an apparently innocuous latency, and/or establish conditions that are conducive to the rescue of the integrated viral genome. The viral replication (Rep) proteins control and direct every known aspect of the viral life cycle and have been shown to tightly control all AAV2 promoters. In addition, a number of heterologous promoters are repressed by the AAV2 Rep proteins. Here, we demonstrate that Rep proteins efficiently repress expression from the target site PPP1R12C promoter. We find evidence that this repression employs mechanisms similar to those described for Rep-mediated AAV2 p5 promoter regulation. Furthermore, we show that the repression of the cellular target site promoter is based on two distinct mechanisms, one relying on the presence of a functional Rep binding motif within the 5′ untranslated region (UTR) of PPP1R12C, whereas the second pathway requires only an intact nucleoside triphosphate (NTP) binding site within the Rep proteins, indicating the possible reliance of this pathway on interactions of the Rep proteins with cellular proteins that mediate or regulate cellular transcription.
publisher	American Society for Microbiology
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135950/
_version_	1613125115199881216

Adeno-Associated Virus Rep Represses the Human Integration Site Promoter by Two Pathways That Are Similar to Those Required for the Regulation of the Viral p5 Promoter

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