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Amplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites
Published on: March 22, 2016
Small tumor virus genomes are integrated near nuclear matrix attachment regions in transformed cells
K A Shera1, C A Shera, J K McDougall
1Cancer Biology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Abstract:
More than 15% of human cancers have a viral etiology. In benign lesions induced by the small DNA tumor viruses, viral genomes are typically maintained extrachromosomally. Malignant progression is often associated with viral integration into host cell chromatin. To study the role of viral integration in tumorigenesis, we analyzed the positions of integrated viral genomes in tumors and tumor cell lines induced by the small oncogenic viruses, including the high-risk human papillomaviruses, hepatitis B virus, simian virus 40, and human T-cell leukemia virus type 1. We show that viral integrations in tumor cells lie near cellular sequences identified as nuclear matrix attachment regions (MARs), while integrations in nonneoplastic cells show no significant correlation with these regions. In mammalian cells, the nuclear matrix functions in gene expression and DNA replication. MARs play varied but poorly understood roles in eukaryotic gene expression. Our results suggest that integrated tumor virus genomes are subject to MAR-mediated transcriptional regulation, providing insight into mechanisms of viral carcinogenesis. Furthermore, the viral oncoproteins serve as invaluable tools for the study of mechanisms controlling cellular growth. Similarly, our demonstration that integrated viral genomes may be subject to MAR-mediated transcriptional effects should facilitate elucidation of fundamental mechanisms regulating eukaryotic gene expression.
Insights
Viral integration near nuclear matrix attachment regions (MARs) in tumor cells suggests MARs regulate viral gene expression, offering insights into viral carcinogenesis and eukaryotic gene regulation.
Area of Science:
- Virology
- Molecular Biology
- Cancer Research
Background:
- Over 15% of human cancers are linked to viral infections.
- Benign viral lesions typically feature extrachromosomal viral genomes.
- Malignant transformation often involves viral genome integration into host DNA.
Purpose of the Study:
- To investigate the role of viral integration in tumorigenesis.
- To analyze the genomic locations of integrated viral DNA in tumors and cell lines.
- To understand the relationship between viral integration and host cell chromatin.
Main Methods:
- Analysis of integrated viral genome positions in tumors and cell lines induced by oncogenic viruses (HPVs, HBV, SV40, HTLV-1).
- Comparison of integration sites in neoplastic versus non-neoplastic cells.
- Identification of host cell sequences near integration sites, specifically nuclear matrix attachment regions (MARs).
Main Results:
- Viral integrations in tumor cells were found to be located near MARs.
- Integrations in non-neoplastic cells did not show a significant correlation with MARs.
- This suggests MARs may influence the transcriptional regulation of integrated viral genomes.
Conclusions:
- Integrated tumor virus genomes appear to be subject to MAR-mediated transcriptional regulation.
- This finding provides insight into the mechanisms of viral carcinogenesis.
- The study also sheds light on fundamental mechanisms regulating eukaryotic gene expression.
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