A5033883424- Cervical Cancer and HPV Research
- Virus-based gene therapy research
- Cancer-related Molecular Pathways
- Protein Tyrosine Phosphatases
- DNA Repair Mechanisms
- Head and Neck Cancer Studies
- interferon and immune responses
- RNA modifications and cancer
- Herpesvirus Infections and Treatments
- Molecular Biology Techniques and Applications
- Veterinary Oncology Research
- Hepatitis B Virus Studies
- T-cell and Retrovirus Studies
- Infectious Diseases and Mycology
- Microbial infections and disease research
- Animal Virus Infections Studies
- Genetic factors in colorectal cancer
- NF-κB Signaling Pathways
- Polyomavirus and related diseases
- Ubiquitin and proteasome pathways
- Vector-Borne Animal Diseases
- Animal Disease Management and Epidemiology
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- PARP inhibition in cancer therapy
Virginia Commonwealth University
2016-2025
VCU Massey Comprehensive Cancer Center
2016-2024
Virginia Cancer Institute
2016-2024
Philips (United States)
2022
University of Colorado Boulder
2022
Children's Hospital of Richmond at VCU
2019
University of Richmond
2019
Philips (Finland)
2019
University of Glasgow
2002-2014
MRC University of Glasgow Centre for Virus Research
2011-2012
Human papillomavirus (HPV) DNA is detected in up to 80% of oropharyngeal carcinomas (OPC) and this HPV positive disease has reached epidemic proportions. To increase our understanding the disease, we investigated status HPV16 genome HPV-positive head neck cancers (HNC). Raw RNA-Seq Whole Genome Sequence data from The Cancer Atlas HNC samples were analyzed gain a full for these tumors. Several remarkable novel observations made following analysis. Firstly, there are three main states tumors...
Fewer than half of children with high-risk neuroblastoma survive. Many these tumors harbor high-level amplification MYCN, which correlates poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA paradoxical, MYCN-driven upregulation NOXA. Screening for enhancers...
Significance Human papillomaviruses (HPV) uncouple proliferation from differentiation to enable virus replication in epithelial cells. HPV E7 proteins are well established promote by binding and inactivating retinoblastoma family other cell cycle inhibitors. However, mechanisms which high-risk oncoproteins inhibit have not been defined. This paper identifies a mechanism keratinocyte differentiation. The inhibition of requires degradation the cellular protein PTPN14 E7, this is related...
ABSTRACT To replicate the double-stranded human papillomavirus 16 (HPV16) DNA genome, viral proteins E1 and E2 associate with origin of replication, can also regulate transcription from adjacent promoters. interacts host in order to both replication; TopBP1 Brd4 are cellular that interact HPV16 E2. Previous work mutants demonstrated requirement for transactivation properties E2, while is required replication induced by association E1. More-recent studies have implicated regulation Here, we...
We previously reported identifying three categories of HPV16-positive head and neck tumors based on The Cancer Genome Atlas (TCGA) RNA DNA sequence data. Category 1 had truly integrated HPV16 genomes, category 2 simple episomal 3 novel episomes that were a hybrid between viral human DNA. Using our categorization, we investigated in this study survival patients with versus tumors. TCGA RNA-Seq reads used to quantify HPV E2 E7 gene expression, which was as marker for integration. results...
Human papillomaviruses are pathogens that cause a host of diseases ranging from benign warts to cancers. There no therapeutics available for combating these directly target viral proteins or processes; therefore, we must enhance our understanding HPV life cycles assist with identifying novel treatments.
ABSTRACT The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. degraded through ubiquitination mediated by cullin 1 (CUL1) the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, proteins are maintained at high levels in most HPV-positive cells. A previous proteomics study has shown that UBE2L3 CUL1 increased knockdown of E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have...
ABSTRACT An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 BRD4 is required for plasmid segregation function. The E2-TopBP1 promotes increased mitotic protein levels in U2OS N/Tert-1 cells, as well foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces stability here we demonstrate that acetylation occurs during mitosis a interacting-dependent manner, promoting stabilization. p300 mediates due to switching off function...
The human papillomavirus (HPV) transcription/replication factor E2 is essential for the life cycle of HPVs. protein binds to DNA target sequences in viral long control regions regulate transcription genome. It also enhances replication by interacting with E1 and recruiting it origin may play a more direct role replication. cellular proteins which interacts carry out these functions are largely unknown. To identify yeast two-hybrid screen was carried domain HPV16 E2. This identified several...
Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number strategies inhibit ATM- and ATR-dependent signaling pathways during Recent work suggests that Ad5 E4orf3 protein prevents ATR activation through its ability mislocalize MRN complex. Here we provide evidence indicate Ad12 different strategy from ATR. We show utilizes CUL2/RBX1/elongin C-containing ubiquitin ligase promote proteasomal degradation activator...
Human papillomaviruses (HPV) replicate their genomes in differentiating epithelium using the viral proteins E1 and E2 association with host proteins. While roles of this process are understood, factors involved how they interact regulate E1-E2 not. Our previous work identified replication repair factor TopBP1 as an partner protein essential for optimal life cycle. The role DNA is regulated by class III deacetylase SIRT1; activation damage response prevents SIRT1 deacetylation TopBP1,...
Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority anogenital and oropharyngeal cancers. Downregulation innate immune genes (IIGs) by HPV to promote viral life cycle is well documented; E6 E7 known repressors these genes. More recently, we demonstrated that E2 could also repress IIGs. These studies have been carried out cells overexpressing proteins, further investigate role individual proteins this repression, introduced stop codons into and/or...
Human papillomaviruses (HPVs) are causative agents in ano-genital and oropharyngeal cancers. The virus must reprogram host gene expression to promote infection, E6 E7 contribute this via the targeting of cellular transcription factors, including p53 pRb, respectively. HPV16 E2 protein regulates U2OS cells, study, we extend these observations into telomerase reverse transcriptase (TERT) immortalized oral keratinocytes (NOKs) that capable supporting late stages life cycle. We observed...
Abstract Therapeutic innovation for human papilloma virus‐related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models the absence of accurate biomarkers. Our study establishes first well‐characterized panel patient‐derived xenografts (PDXs) organoids from HPV+ HNSCCs while determining fidelity to distinguishing genetic features this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple HNSCC lost in...
The membrane-associated RING-CH-type finger ubiquitin ligase MARCHF8 is a human homolog of the viral ligases Kaposi’s sarcoma herpesvirus K3 and K5 that promote host immune evasion. Previous studies have shown ubiquitinates several receptors, such as major histocompatibility complex II CD86. While papillomavirus (HPV) does not encode any ligase, oncoproteins E6 E7 are known to regulate ligases. Here, we report expression upregulated in HPV-positive head neck cancer (HNC) patients but...
HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related in developed world. HPV16 ∼90 % of OPCs, with episomal genomes majority cases. Most existing HPV16+ lines derive from outside oropharynx harbor integrated genomes. Thus, there need for OPC preclinical models to evaluate standard experimental therapeutics presence oncogenic drivers. Here we characterize genome structures eight patient-derived xenografts (PDXs),...
Abstract Background Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed identify molecular traits that distinguish recurrence-prone tumors. Methods 50 HPV+ OPSCCs later recurred (cases) and non-recurrent controls matched for stage, therapy, smoking history were RNA-sequenced. Groups compared by gene set enrichment analysis, select differences...
Human papillomavirus type 16 (HPV16) E2 regulates transcription from and replication of the viral genome, in association with cellular factors. HPV16 interacts functionally TopBP1, a protein essential for initiation cellular, potentially viral, DNA replication. This report demonstrates that absence TopBP1 results redistribution into an alternative complex, resulting enhanced affinity chromatin. does not significantly alter ability to either activate or repress transcription. We also show...
ABSTRACT In human papillomavirus DNA replication, the viral protein E2 forms homodimers and binds to 12-bp palindromic sequences surrounding origin of replication. Via a protein-protein interaction, it then recruits helicase E1 an A/T-rich whereupon dihexamer forms, resulting in replication initiation. order carry out proteins must interact with host factors that are currently not all known. An attractive cellular candidate for regulating is TopBP1, known interactor protein. mammalian TopBP1...
// Michael R. Evans 1 , Claire D. James Oonagh Loughran Tara J. Nulton Xu Wang Molly L. Bristol Brad Windle 1,2 and Iain M. Morgan Department of Oral Craniofacial Molecular Biology, VCU Philips Institute for Health Research, Virginia Commonwealth University School Dentistry, Richmond, VA, USA 2 Massey Cancer Center, Correspondence to: Morgan, email: Keywords : head neck cancer, human papillomavirus, life-cycle, the cancer genome atlas, keratinocytes Received May 07, 2017 Accepted 17,...
HPV16 is the major viral human carcinogen responsible for between 3 and 4% of all cancers worldwide. Following infection, this virus activates DNA damage response (DDR) to promote its life cycle recruits DDR proteins replicating in order facilitate homologous recombination during replication. This promotes production viable progeny. Our understanding how replication interacts with remains incomplete. Here, we demonstrate that cellular deacetylase SIRT1, which a part E1-E2 complex, regulates...