Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation

Hong, Siqi; Xu, Jianrong; Li, Yan; Andrade, Jorge; Hoover, Paul; Kaminski, Paul J.; Laimins, Laimonis A.

doi:10.1038/s41388-018-0633-1

Cited by 14 publications

(17 citation statements)

References 67 publications

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“…HPV-positive cells with either ATR or TopBP1 knockdown (24) remain proliferative and do not become growth arrested. We screened downstream targets of TopBP1 by RNA-seq approaches and found a number of potential downstream targets related to immune response (24), which are also detected in ATR knockdown cells (Fig. 6a).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, functional enrichment analysis was performed with Qiagen's Ingenuity Pathway Analysis (IPA). The work of TopBP1 knockdown RNA-seq has been published in our previous work (24).…”

Section: Methodsmentioning

confidence: 99%

“…Once activated, ATR triggers the activation of downstream factors such as CHK1 (21), BRCA1 (22), and minichromosome maintenance (MCM) proteins (23), which leads to cell cycle exit or repair of DNA breaks. In contrast to the effect of ATM inhibition, suppression of the ATR pathway significantly impairs both HPV amplification and stable maintenance replication (16,18,24).…”

mentioning

confidence: 99%

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Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

Hong

Kaminski

et al. 2020

mBio

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High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway, and this is required for viral replication. In fibroblasts, activated ATR regulates transcription of inflammatory genes through its negative effects on the autophagosome cargo protein p62. In addition, suppression of p62 results in increased levels of the transcription factor GATA4, leading to cellular senescence. In contrast, in HPV-positive keratinocytes, we observed that activation of ATR resulted in increased levels of phosphorylated p62, which in turn lead to reduced levels of GATA4. Knockdown of ATR in HPV-positive cells resulted in decreased p62 phosphorylation and increased GATA4 levels. Transcriptome sequencing (RNA-seq) analysis of HPV-positive cells identified inflammatory genes and interferon factors as negative transcriptional targets of ATR. Furthermore, knockdown of p62 or overexpression of GATA4 in HPV-positive cells leads to inhibition of viral replication. These findings identify a novel role of the ATR/p62 signaling pathway in HPV-positive cells. IMPORTANCE High-risk human papillomaviruses (HPVs) infect epithelial cells and induce viral genome amplification upon differentiation. HPV proteins activate the ATR DNA damage repair pathway, and this is required for HPV genome amplification. In the present study, we show that HPV-induced ATR activation also leads to suppression of expression of inflammatory response genes. This suppression results from HPV-induced phosphorylation of the autophagosome cargo protein p62 which regulates the levels of the transcription factor GATA4. Activation of p62 in normal fibroblasts results in senescence, but this is not seen in HPV-positive keratinocytes. Importantly, knockdown of p62 or overexpression of GATA4 in HPV-positive cells abrogates viral replication. This study demonstrates that activation of ATR in HPV-positive cells triggers a p62-directed pathway inducing suppression of inflammatory gene expression independent of DNA repair and facilitating HPV replication.

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Section: Discussionmentioning

confidence: 99%

“…Finally, functional enrichment analysis was performed with Qiagen's Ingenuity Pathway Analysis (IPA). The work of TopBP1 knockdown RNA-seq has been published in our previous work (24).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

Hong

Kaminski

et al. 2020

mBio

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“…Transcription regulation plays key roles in HPV productive life cycle. For example, the transcription factor family of p63 and p73 is critical for HPV genome amplification [ 53 , 54 ]. Other transcription factors that regulate HPV viral transcription were summarized in the previous review [ 55 ].…”

Section: Hpv Life Cyclementioning

confidence: 99%

The Role of Ataxia Telangiectasia Mutant and Rad3-Related DNA Damage Response in Pathogenesis of Human Papillomavirus

Luo

Hong

2020

Pathogens

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Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only effective in individuals with no prior HPV infection. Thus, it is still important to understand the HPV life cycle and in particular the association of HPV with human pathogenesis. HPV production requires activation of the DNA damage response (DDR), which is a complex signaling network composed of multiple sensors, mediators, transducers, and effectors that safeguard cellular DNAs to maintain the host genome integrity. In this review, we focus on the roles of the ataxia telangiectasia mutant and Rad3-related (ATR) DNA damage response in HPV DNA replication. HPV can induce ATR expression and activate the ATR pathway. Inhibition of the ATR pathway results in suppression of HPV genome maintenance and amplification. The mechanisms underlying this could be through various molecular pathways such as checkpoint signaling and transcriptional regulation. In light of these findings, other downstream mechanisms of the ATR pathway need to be further investigated for better understanding HPV pathogenesis and developing novel ATR DDR-related inhibitors against HPV infection.

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“…TopBP1 is a scaffold protein containing 9 BRCT (BRCA1 carboxyl terminus) domains and is involved in many aspects of nucleic acid metabolism, including DNA replication and repair [ 61 ]. Studies from several groups, including ours, have indicated that TopBP1 is important in HPV replication [ 43 , 44 , 45 , 48 , 62 , 63 ]. TopBP1 is an essential protein; therefore we sought to identify host enzymes that regulate TopBP1 as potential modulators of E1–E2 replication.…”

Section: Using the Hpv16 Replication Assay To Study Lesions In Hosmentioning

confidence: 99%

Using a Human Papillomavirus Model to Study DNA Replication and Repair of Wild Type and Damaged DNA Templates in Mammalian Cells

Das

Bristol

Pichierri

et al. 2020

IJMS

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Human papillomaviruses have 8kbp DNA episomal genomes that replicate autonomously from host DNA. During initial infection, the virus increases its copy number to 20–50 copies per cell, causing torsional stress on the replicating DNA. This activates the DNA damage response (DDR) and HPV replicates its genome, at least in part, using homologous recombination. An active DDR is on throughout the HPV life cycle. Two viral proteins are required for replication of the viral genome; E2 binds to 12bp palindromic sequences around the A/T rich origin of replication and recruits the viral helicase E1 via a protein–protein interaction. E1 forms a di-hexameric complex that replicates the viral genome in association with host factors. Transient replication assays following transfection with E1–E2 expression plasmids, along with an origin containing plasmid, allow monitoring of E1-E2 replication activity. Incorporating a bacterial lacZ gene into the origin plasmid allows for the determination of replication fidelity. Here we describe how we exploited this system to investigate replication and repair in mammalian cells, including using damaged DNA templates. We propose that this system has the potential to enhance the understanding of cellular components involved in DNA replication and repair.

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Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation

Cited by 14 publications

References 67 publications

Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

The Role of Ataxia Telangiectasia Mutant and Rad3-Related DNA Damage Response in Pathogenesis of Human Papillomavirus

Using a Human Papillomavirus Model to Study DNA Replication and Repair of Wild Type and Damaged DNA Templates in Mammalian Cells

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