Loss of gene function as a consequence of human papillomavirus DNA integration

@article{Schmitz2012LossOG,
  title={Loss of gene function as a consequence of human papillomavirus DNA integration},
  author={Martina Schmitz and Corina Driesch and Katrin Beer-Grondke and Lars Jansen and Ingo B Runnebaum and Matthias D{\"u}rst},
  journal={International Journal of Cancer},
  year={2012},
  volume={131}
}
Integration of the human papillomavirus (HPV) genome into the host chromatin is a characteristic step in cervical carcinogenesis. Integration ensures constitutive expression of the viral oncogenes E6 and E7 which drive carcinogenesis. However, integration has also an impact on host DNA. There is increasing evidence that integration not only occurs in fragile sites and translocation breakpoints but also in transcriptionally active regions. Indeed, a substantial number of integration sites… 
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TLDR
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Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis
TLDR
This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a ‘cancer-causing gene’ is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.
Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV‐related cervical carcinogenesis
TLDR
It was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation and provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction.
Preferential sites for the integration and disruption of human papillomavirus 16 in cervical lesions.
  • H. Li, Yi Yang, +8 authors B. Zhu
  • Biology, Medicine
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
  • 2013
TLDR
There are sites of preferential HPV 16 integration, and the integration sites tend to be located in repetitive regions of the host genome, and some sites are found near cancer-relevant genes.
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References

SHOWING 1-10 OF 51 REFERENCES
Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract
TLDR
It is confirmed that HPV integration sites are randomly distributed over the whole genome with a clear predilection for genomic fragile sites, and no evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.
A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques
TLDR
Analysis of integration sites of HPV16 and 18 genomes in 21 anogenital precancerous and cancerous lesions and amplification of papilloma virus oncogene transcripts assay suggests that in the progression of cervical preneoplasia to invasive carcinomas, integration of viral genomes occurs only at single or few chromosomal loci in a given cell clone.
DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri
TLDR
Data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia and support the sequential concept.
Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts
TLDR
Experimental data provide evidence that integration could result in increased levels of oncogene (E6/E7) transcripts and do not support the hypothesis that HPV integration invariably results in high levels ofoncogene transcripts.
Prognostic significance of HPV physical status and integration sites in cervical cancer.
TLDR
This is the first study from India to provide the physical status of HPV16 and HPV 18 in cervical cancers, to assess their prognostic importance and to identify FRA and MiRNAs' near HPV integration sites.
Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes
TLDR
It is demonstrated that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein.
Mechanism of Genomic Instability in Cells Infected with the High-Risk Human Papillomaviruses
TLDR
The current study indicates that the E1- and E2-dependent DNA replication from the integrated HPV origin follows the “onion skin”–type replication mode and generates a heterogeneous population of replication intermediates.
The majority of viral-cellular fusion transcripts in cervical carcinomas cotranscribe cellular sequences of known or predicted genes.
TLDR
The influence of HPV integration on host gene expression may not be a rare effect and should encourage more detailed analyses, as it is tempting to speculate that as yet unknown fragile sites may be identified on the basis of HPV Integration hotspots.
Common fragile sites are preferential targets for HPV16 integrations in cervical tumors
TLDR
The data suggest that cellular genes, such as Notch 1, are disrupted by the HPV16 integrations, which may contribute to the malignant phenotype.
APM‐1, a novel human gene, identified by aberrant co‐transcription with papillomavirus oncogenes in a cervical carcinoma cell line, encodes a BTB/POZ‐zinc finger protein with growth inhibitory activity
TLDR
The identification of a novel human gene, named APM‐1, which is co‐transcribed with the HPV68 E6 and E7 genes and is present in the 3′‐cellular part of the ME180 viral–cellular fusion transcripts.
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