STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication

ABSTRACT The life cycle of high-risk human papillomaviruses (HPVs) is dependent upon epithelial differentiation. Following infection of basal cells, HPV genomes are stably maintained at low copy numbers, and productive replication or amplification is restricted to highly differentiated suprabasal ce...

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Autores principales:	Shiyuan Hong, Shouqiang Cheng, Andre Iovane, Laimonis A. Laimins
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3c9b0d4e0994485684d093a2d582d9a0
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spelling	oai:doaj.org-article:3c9b0d4e0994485684d093a2d582d9a02021-11-15T15:41:23ZSTAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication10.1128/mBio.02006-152150-7511https://doaj.org/article/3c9b0d4e0994485684d093a2d582d9a02015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02006-15https://doaj.org/toc/2150-7511ABSTRACT The life cycle of high-risk human papillomaviruses (HPVs) is dependent upon epithelial differentiation. Following infection of basal cells, HPV genomes are stably maintained at low copy numbers, and productive replication or amplification is restricted to highly differentiated suprabasal cells. In high-risk HPV infections, the ATM pathway is constitutively activated in the absence of external DNA-damaging agents and is required for productive viral replication. The ataxia telangiectasia (ATM) pathway repairs double-strand breaks in DNA, while the ataxia telangiectasia and Rad3-related (ATR) pathway targets single-strand breaks. Our studies show that the ATR pathway, like the ATM pathway, is activated in HPV-positive cells and that inhibitors of ATR or CHK1 phosphorylation block both amplification and late viral gene expression in differentiated cells while moderately reducing stable copy numbers in undifferentiated cells. TopBP1 is a critical upstream activator of the ATR pathway and is expressed at elevated levels in HPV-positive cells. This increased expression of TopBP1 is necessary for ATR/CHK1 activation in HPV-positive cells, and knockdown blocks amplification. Furthermore, TopBP1 activation is shown to be regulated at the level of transcription initiation by the innate immune regulator STAT-5, which is activated by HPV proteins. STAT-5 has also been shown to be a regulator of the ATM response, demonstrating that these two pathways are coordinately regulated in HPV-positive cells. These findings identify a novel link between the innate immune response and activation of the ATR DNA damage response in regulating the life cycle of high-risk HPVs. IMPORTANCE High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers, as well as many oral cancers. HPVs infect epithelial cells and restrict productive viral replication or amplification and virion production to differentiated cells. Our studies demonstrate that HPVs activate the ATR single-strand DNA repair pathway and this activation is necessary for HPV genome amplification. The innate immune regulator STAT-5 is shown to regulate transcription of the ATR binding factor TopBP1, and this is critical for the induction of the ATR pathway. Our study identifies important links between innate immune signaling, the ATR DNA damage pathway, and productive HPV replication that may lead to the characterization of new targets for the development of therapeutics to treat HPV-induced infections.Shiyuan HongShouqiang ChengAndre IovaneLaimonis A. LaiminsAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Shiyuan Hong Shouqiang Cheng Andre Iovane Laimonis A. Laimins STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
description	ABSTRACT The life cycle of high-risk human papillomaviruses (HPVs) is dependent upon epithelial differentiation. Following infection of basal cells, HPV genomes are stably maintained at low copy numbers, and productive replication or amplification is restricted to highly differentiated suprabasal cells. In high-risk HPV infections, the ATM pathway is constitutively activated in the absence of external DNA-damaging agents and is required for productive viral replication. The ataxia telangiectasia (ATM) pathway repairs double-strand breaks in DNA, while the ataxia telangiectasia and Rad3-related (ATR) pathway targets single-strand breaks. Our studies show that the ATR pathway, like the ATM pathway, is activated in HPV-positive cells and that inhibitors of ATR or CHK1 phosphorylation block both amplification and late viral gene expression in differentiated cells while moderately reducing stable copy numbers in undifferentiated cells. TopBP1 is a critical upstream activator of the ATR pathway and is expressed at elevated levels in HPV-positive cells. This increased expression of TopBP1 is necessary for ATR/CHK1 activation in HPV-positive cells, and knockdown blocks amplification. Furthermore, TopBP1 activation is shown to be regulated at the level of transcription initiation by the innate immune regulator STAT-5, which is activated by HPV proteins. STAT-5 has also been shown to be a regulator of the ATM response, demonstrating that these two pathways are coordinately regulated in HPV-positive cells. These findings identify a novel link between the innate immune response and activation of the ATR DNA damage response in regulating the life cycle of high-risk HPVs. IMPORTANCE High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other anogenital cancers, as well as many oral cancers. HPVs infect epithelial cells and restrict productive viral replication or amplification and virion production to differentiated cells. Our studies demonstrate that HPVs activate the ATR single-strand DNA repair pathway and this activation is necessary for HPV genome amplification. The innate immune regulator STAT-5 is shown to regulate transcription of the ATR binding factor TopBP1, and this is critical for the induction of the ATR pathway. Our study identifies important links between innate immune signaling, the ATR DNA damage pathway, and productive HPV replication that may lead to the characterization of new targets for the development of therapeutics to treat HPV-induced infections.
format	article
author	Shiyuan Hong Shouqiang Cheng Andre Iovane Laimonis A. Laimins
author_facet	Shiyuan Hong Shouqiang Cheng Andre Iovane Laimonis A. Laimins
author_sort	Shiyuan Hong
title	STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
title_short	STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
title_full	STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
title_fullStr	STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
title_full_unstemmed	STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication
title_sort	stat-5 regulates transcription of the topoisomerase iiβ-binding protein 1 (topbp1) gene to activate the atr pathway and promote human papillomavirus replication
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/3c9b0d4e0994485684d093a2d582d9a0
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STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication

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