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Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome
Moon Kyoo Jang1, Kui Shen2, Alison A McBride1
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Abstract:
It has long been recognized that oncogenic viruses often integrate close to common fragile sites. The papillomavirus E2 protein, in complex with BRD4, tethers the viral genome to host chromatin to ensure persistent replication. Here, we map these targets to a number of large regions of the human genome and name them Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin or PEB-BLOCs. PEB-BLOCs frequently contain deletions, have increased rates of asynchronous DNA replication, and are associated with many known common fragile sites. Cell specific fragile sites were mapped in human C-33 cervical cells by FANCD2 ChIP-chip, confirming the association with PEB-BLOCs. HPV-infected cells amplify viral DNA in nuclear replication foci and we show that these form adjacent to PEB-BLOCs. We propose that HPV replication, which hijacks host DNA damage responses, occurs adjacent to highly susceptible fragile sites, greatly increasing the chances of integration here, as is found in HPV-associated cancers.
Insights
Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin (PEB-BLOCs) are genomic regions targeted by papillomavirus. These sites, prone to DNA damage, facilitate viral integration and HPV-associated cancers.
Area of Science:
- Genomics
- Virology
- Cancer Biology
Background:
- Oncogenic viruses frequently integrate near common fragile sites.
- The papillomavirus E2 protein, with BRD4, anchors viral DNA to host chromatin for replication.
Purpose of the Study:
- To map the genomic targets of papillomavirus E2 and BRD4 interaction.
- To investigate the association between these targets and fragile sites in HPV infection.
Main Methods:
- Genome-wide mapping of Persistent E2 and BRD4-Broad Localized Enrichments of Chromatin (PEB-BLOCs).
- FANCD2 ChIP-chip in human C-33 cervical cells to map fragile sites.
- Microscopy to visualize viral DNA replication foci in HPV-infected cells.
Main Results:
- PEB-BLOCs were identified as large genomic regions frequently containing deletions and asynchronous replication.
- PEB-BLOCs are strongly associated with common fragile sites.
- HPV replication foci form adjacent to PEB-BLOCs, suggesting a link to fragile site susceptibility.
Conclusions:
- Papillomavirus replication occurs near susceptible fragile sites (PEB-BLOCs).
- This proximity increases the likelihood of viral integration at these sites.
- The findings provide a mechanism for viral integration in HPV-associated cancers.
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