Multiple Roles of Brd4 in the Infectious Cycle of Human Papillomaviruses

McBride, Alison A.; Warburton, Alix; Khurana, Simran

doi:10.3389/fmolb.2021.725794

Cited by 14 publications

(20 citation statements)

References 130 publications

(226 reference statements)

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“…Brd4 is a chromatin scaffold protein that modulates transcriptional initiation and elongation and is a major component of super-enhancers 74 . Brd4 is also important at multiple stages of the HPV infectious cycle 75 , binds to common fragile sites in C33-A cells 26 , and is important for tethering HPV genomes to mitotic chromatin 76,77 . Brd4 is enriched at the HPV16 integration site/super-enhancer in W12 cells and inhibition of Brd4 binding reduces E6/E7 transcription and cell growth 24 .…”

Section: Discussionmentioning

confidence: 99%

Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs

Warburton

Markowitz

Katz

et al. 2021

Preprint

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Oncogenic human papillomavirus (HPV) genomes are often integrated into host chromosomes in HPV-associated cancers. HPV genomes are integrated either as a single copy, or as tandem repeats of viral DNA interspersed with, or without, host DNA. Integration occurs frequently in common fragile sites susceptible to tandem repeat formation, and the flanking or interspersed host DNA often contains transcriptional enhancer elements. When co-amplified with the viral genome, these enhancers can form super-enhancer-like elements that drive high viral oncogene expression. Here, we compiled highly curated datasets of HPV integration sites in cervical (CESC) and head and neck squamous cell carcinoma (HNSCC) cancers and assessed the number of breakpoints, viral transcriptional activity, and host genome copy number at each insertion site. Tumors frequently contained multiple distinct HPV integration sites, but often only one driver site that expressed viral RNA. Since common fragile sites and active enhancer elements are cell-type specific, we mapped these regions in cervical cell lines using FANCD2 and Brd4/H3K27ac ChIP-seq, respectively. Large enhancer clusters, or super-enhancers, were also defined using the Brd4/H3K27ac ChIP-seq dataset. HPV integration breakpoints were enriched at both FANCD2-associated fragile sites, and enhancer-rich regions, and frequently showed adjacent focal DNA amplification in CESC samples. We identified recurrent integration hotspots that were enriched for super-enhancers, some of which function as regulatory hubs for cell-identity genes. We propose that during persistent infection, extrachromosomal HPV minichromosomes associate with these transcriptional epicenters, and accidental integration could promote viral oncogene expression and carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs

Warburton

Markowitz

Katz

et al. 2021

Preprint

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“…These interactions facilitate the internalization of the virus into the host cell. 12,19,20,22,[40][41][42] HPV has evolved strategies to evade the host immune response. The virus can inhibit interferon signaling, interfere with antigen presentation, and modulate immune cell functions.…”

Section: Hpv Types Global Distributionmentioning

confidence: 99%

“…By evading immune detection and clearance, HPV can establish persistent infections and increase the risk of disease progression. 12,19,22,42 Once inside the host cell, HPV relies on the host cell machinery for gene expression. The viral genome is replicated and transcribed using host cell enzymes.…”

Section: Hpv Types Global Distributionmentioning

confidence: 99%

Human Papillomavirus Infection: Epidemiology, Biology, Host Interactions, Cancer Development, Prevention, and Therapeutics

Wolf

2023

Preprint

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Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. It is caused by the human papillomavirus, a DNA virus that infects epithelial cells in various mucous membranes and skin surfaces. HPV can be categorized into high-risk and low-risk types based on their association with the development of certain cancers. High-risk HPV types, such as HPV-16 and HPV-18, are known to be oncogenic and are strongly associated with the development of cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancers. These types of HPV can persist in the body for an extended period and, in some cases, lead to the formation of precancerous lesions that may progress to cancer if left untreated. Low-risk HPV types, such as HPV-6 and HPV-11, are not typically associated with cancer but can cause benign conditions like genital warts. Genital warts are characterized by the growth of small, cauliflower-like bumps on the genital and anal areas. Although not life-threatening, they can cause discomfort and psychological distress. HPV is primarily transmitted through sexual contact, including vaginal, anal, and oral sex. It can also be transmitted through non-penetrative sexual activities that involve skin-to-skin contact. In addition to sexual transmission, vertical transmission from mother to child during childbirth is possible but relatively rare. Prevention of HPV infection includes vaccination and safe sexual practices. HPV vaccines, such as Gardasil and Cervarix, are highly effective in preventing infection with the most common high-risk HPV types. These vaccines are typically administered to adolescents and young adults before they become sexually active. Safe sexual practices, such as consistent and correct condom use and limiting the number of sexual partners, can also reduce the risk of HPV transmission. Diagnosis of HPV infection can be challenging because the infection is often asymptomatic, especially in men. In women, HPV testing can be done through cervical screening programs, which involve the collection of cervical cells for analysis. Abnormal results may lead to further diagnostic procedures, such as colposcopy or biopsy, to detect precancerous or cancerous changes. Overall, HPV infection is a prevalent sexually transmitted infection with significant implications for public health. Vaccination, regular screening, and early treatment of precancerous lesions are key strategies to reduce the burden of HPV-related diseases and their associated complications. Education and awareness about HPV and its prevention are crucial in promoting optimal sexual health. This study aimed to carry out a literature review considering several aspects involving HPV infection: Global distribution, prevalence, biology, host interactions, cancer development, prevention, therapeutics, coinfection with other viruses, coinfection with bacteria, association with head and neck squamous cell carcinomas (HNSCC), and association with anal cancer.

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“…The early region encodes proteins (E1-E8) necessary for viral replication and host cell transformation, the late region encodes the L1 and L2 capsid proteins, while the non-coding upstream regulatory region (URR) contains binding sites for viral DNA transcription and regulates DNA replication. 3,4 The early E1 and E2 proteins, as well as the late L1 and L2 proteins, comprise the bulk of papillomaviruses genome and are present in all sequenced papillomaviruses (PVs). 5,6 PVs are classified into genera, species, and types using the International Committee on Virus Taxonomy's (ICTV) standard, based on pairwise nucleotide sequence identity of the main capsid protein, L1 ORF.…”

Section: Introductionmentioning

confidence: 99%

“…Their genome is around 8 kilobase in size and is divided into three functional regions. The early region encodes proteins (E1‐E8) necessary for viral replication and host cell transformation, the late region encodes the L1 and L2 capsid proteins, while the non‐coding upstream regulatory region (URR) contains binding sites for viral DNA transcription and regulates DNA replication 3,4 . The early E1 and E2 proteins, as well as the late L1 and L2 proteins, comprise the bulk of papillomaviruses genome and are present in all sequenced papillomaviruses (PVs) 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Novel equid papillomavirus from domestic donkey

Ikechukwu

Qin

Zhang

et al. 2023

Equine Veterinary Journal

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BackgroundPapillomaviruses can be of great medical importance as they infect humans and animals such as Equus species, other livestock and pets. They are responsible for several papillomas and benign tumours in their host.ObjectivesTo describe a novel equid papillomavirus detected in oral swab samples collected from donkeys (Equus asinus) found on the Northwest plateau of China.Study designCross‐sectional.MethodsSwab samples collected from the oral mucosa of 32 donkeys in the Gansu Province of China, were subjected to viral metagenomic analysis to detect the presence of Papillomavirus. After de novo assembly, a novel papillomavirus genome designated as Equus asinus papillomavirus 3 (EaPV3) was identified in the studied samples. Additional bioinformatic analysis of the assembled genome was done using the Geneious prime software (version 2022.0.2).ResultsThe complete circular genome of EaPV3 is 7430 bp in length with a GC content of 50.8%. The genome was predicted to contain five ORFs coding for three early proteins (E7, E1, and E2) and two late proteins (L1 and L2). Phylogenic analysis of the nucleotide sequences of the concatenated amino acid sequences of the E1E2L1L2 genes revealed that EaPV3 is most closely related to Equus asinus papillomavirus 1 (EaPV1). The genome analysis of EaPV3 revealed similar genome organisation with other equine papillomavirus and the presence of E7 papillomavirus oncoprotein.Main limitationsSince there were no warts in the oral cavity of the donkeys in this study, and no biopsy samples taken, we are unable to conclusively link the novel virus to any clinical condition in the donkeys.ConclusionsThe Comparative characterisation of EaPV3 and its closest relatives, as well as phylogenetic analysis demonstrated that it is a novel virus specie that clusters within the Dyochipapilloma PV genus.

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Multiple Roles of Brd4 in the Infectious Cycle of Human Papillomaviruses

Cited by 14 publications

References 130 publications

Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs

Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs

Human Papillomavirus Infection: Epidemiology, Biology, Host Interactions, Cancer Development, Prevention, and Therapeutics

Novel equid papillomavirus from domestic donkey

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