Regulation of human genome expression and RNA splicing by human papillomavirus 16 E2 protein

Gauson, Elaine J.; Windle, Brad; Donaldson, Mary; Caffarel, María M.; Dornan, Edward S.; Coleman, Nicholas; Herzyk, Paweł; Henderson, Scott C.; Wang, Xu; Morgan, Iain M.

doi:10.1016/j.virol.2014.07.022

Cited by 33 publications

(42 citation statements)

References 50 publications

(68 reference statements)

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“…This exciting finding implies that because the relative levels of SRSFs in a cell determine alternative splicing outcomes and thus the overall protein profile, E2 may control the cellular environment via control of SRSF expression to optimize viral replication. In support of this, a recent study has revealed that overexpression of E2 in U2OS osteosarcoma cells resulted in very significant changes in cellular alternative splicing, with 522 mRNAs affected (32). Cancer genes and genes encoding proteins involved in cell motility were the most affected.…”

Section: E2 As a Regulator Of Srsfsmentioning

confidence: 80%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle. HUMAN PAPILLOMAVIRUS LIFE CYCLEH uman papillomaviruses (HPVs) are small (ϳ8.0-kbp) circular double-stranded DNA viruses that infect epithelial cells (keratinocytes) (1). There are more than 200 HPV genotypes. For the most part, HPVs of the ␣-genotype group infect mucosal epithelia, while the ␤-genotypes infect predominantly cutaneous epithelia (2). Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia. HR-HPVs are commonly associated with cervical cancer and tumors of other anogenital sites (2). Per annum, worldwide, there are around 500,000 new cases of cervical disease, and around 270,000 women die from cervical cancer. The two most prevalent HR-HPVs are HPV16 and -18, which are targeted by the current HPV vaccines (4). Over the last few decades, epidemic HR-HPV infection, especially in men, has been associated with a significant increase in oropharyngeal cancers (5). Certain cutaneous HPVs can also cause tumors (squamous cell carcinomas) in immunocompromised or immunosuppressed individuals (6). Thus, the causative association of HPV infection with a number of significant cancers indicates that increased understanding of the viral life cycle is essential.The HPV life cycle is intimately linked to epithelial differentiation (Fig. 1A) (2). HPV normally infects dividing cells at the base of the epithelium (basal layer) but completes its life cycle by amplifying progeny DNA genomes in the midepithelial layers (spinous layer) and carrying out viral encapsidation in the uppermost epithelial layer (granular layer) (Fig. 1A). Viral production is achieved through a highly orchestrated and complex viral gene expression program (Fig. 1A) (2). Mature virions are released upon shedding and disintegration of dead superficial epithelial cells into the environment. As a necessity, HPV infection alters the normal differentiation pattern of the epithelium and controls cellular gene expression to support viral re...

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Section: E2 As a Regulator Of Srsfsmentioning

confidence: 80%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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“…Exon array analysis was carried out as described (Gauson et al, 2014). The data was analyzed using Affymetrix Exon array software and core data analysis was performed using Partek genomics suite as described previously (Gauson et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…Recently we reported that HPV16 E2 can regulate transcription from a host genome when expressed stably (Gauson et al, 2014). We hypothesized that an interaction between E2 and Brd4 would be involved in transcriptional regulation of the host chromatin.…”

Section: Introductionmentioning

confidence: 99%

“…There was no reduction in the number of genes that E2 −Brd4 regulated, but there were E2 wt activated genes that depend upon the Brd4 interaction. E2 −Brd4 was also not as compromised as E2 wt in wound healing (Gauson et al, 2014). Overall the results suggest that interaction with Brd4 assists E2 wt in regulating the host genome and in the absence of Brd4 interaction E2 may locate to and regulate other parts of the genome.…”

Section: Introductionmentioning

confidence: 99%

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Failure to interact with Brd4 alters the ability of HPV16 E2 to regulate host genome expression and cellular movement

et al. 2016

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The E2 protein of the carcinogen human papillomavirus 16 (HPV16) regulates replication and transcription of the viral genome in association with viral and cellular proteins. Our previous work demonstrated that E2 can regulate transcription from the host genome. E2 can activate transcription from adjacent promoters when located upstream using E2 DNA binding sequences and this activation is dependent upon the cellular protein Brd4; this report demonstrates that a Brd4 binding E2 mutant alters host genome expression differently from wild type E2. Of particular note is that highly down regulated genes are mostly not affected by failure to interact with Brd4 suggesting that the E2-Brd4 interaction is more responsible for the transcriptional activation of host genes rather than repression. Therefore failure to interact efficiently with Brd4, or altered levels of Brd4, would alter the ability of E2 to regulate the host genome and could contribute to determining the outcome of infection.

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“…The best understood molecular activity of E5 is to enhance signaling from the epidermal growth factor receptor (EGFR) 12 . The viral E2 protein is a transcription factor that regulates viral gene expression, and recently has been found to regulate cellular promoters, as well 57,58 , although E2 does not act as an oncogene. The viral oncoproteins each have numerous other interactions and activities, many of which will be discussed in this chapter 10,55 .…”

Section: The Hpv Life Cyclementioning

confidence: 99%

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Woodby

Scott

Bodily

2016

Progress in Molecular Biology and Translational Science

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Human papillomaviruses (HPV) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection.

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Regulation of human genome expression and RNA splicing by human papillomavirus 16 E2 protein

Cited by 33 publications

References 50 publications

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Failure to interact with Brd4 alters the ability of HPV16 E2 to regulate host genome expression and cellular movement

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

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