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The role of integration in oncogenic progression of HPV-associated cancers

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In these cancers, the extrachromosomal viral genome has often become integrated into the host genome... The integration event is thought to drive oncogenesis by dysregulating expression of the E6 and E7 viral oncogenes, leading to inactivation of critical cell cycle checkpoints and increased genetic instability in the host... It is only when these infected cells differentiate and move towards the surface of the epithelium that high levels of viral DNA are synthesized, packaged in virions, and sloughed from the surface of the epithelium in viral-laden squames... HPVs are often found integrated in premalignant lesions and a range of anogenital and oropharyngeal cancers, but this is not part of the viral life cycle... Continued expression of the E1 and E2 replication proteins from integrated genomes causes focal genomic instability at the integration locus, and in most cases, when complete genomes are tandemly integrated, the internal copies are silenced by DNA methylation... Viral genome integration events usually result in dysregulation of E6 and E7 gene expression compared to that expressed from extrachromosomal viral genomes, and this can be achieved in a number of ways (see Fig 2 and Table 1)... E2 regulation can also be disrupted by methylation of the E2 binding sites in the URR... E6/E7 oncogene expression can also be modulated by epigenetic events that do not directly affect E2 DNA binding... Many different methods have been used to detect integrated viral genomes, and more research is needed to clarify the significance of the observed differential rates of integration and to determine whether HPVs promote oncogenesis by different mechanisms at different anatomical locations... Regions of microhomology (1–10 bp) between viral and human genomic sequences are sometimes found at integration breakpoints, as have AT-rich regions of the genome that have the potential to form stem—loop structures that promote the formation of stalled replication forks during replication stress... There are also examples of HPV integration resulting in insertional mutagenesis and/or potential regulatory effects on neighbouring genes... Increased integration within cancer-associated genes or pathways, including the MYC gene locus, have also been reported... However, this is not a universal phenomenon associated with HPV integration... Therefore, many events and processes contribute to the development of an HPV integration event that is a strong driver of oncogenesis; there are likely many dead-end integration events that fail to produce sufficient E6/E7 oncoproteins to drive clonal expansion of the host cell.

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Models of integration events that promote oncogenesis.The five integration models shown in Table 1 are shown in the diagram, as indicated to the left. URR (upstream regulatory region), and PE (early promoter), are indicated. The light blue circles in the URR represent E2 binding sites, and the dark blue square is the E1 binding site in the origin of replication (ori).
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ppat.1006211.g002: Models of integration events that promote oncogenesis.The five integration models shown in Table 1 are shown in the diagram, as indicated to the left. URR (upstream regulatory region), and PE (early promoter), are indicated. The light blue circles in the URR represent E2 binding sites, and the dark blue square is the E1 binding site in the origin of replication (ori).

Mentions: Viral genome integration events usually result in dysregulation of E6 and E7 gene expression compared to that expressed from extrachromosomal viral genomes, and this can be achieved in a number of ways (see Fig 2 and Table 1). The earliest model proposed that the integration event disrupts the E2 gene, alleviating E2 transcriptional repression of the E6 and E7 promoter and thus driving oncogene expression [13]. E2 regulation can also be disrupted by methylation of the E2 binding sites in the URR [14]. E6/E7 oncogene expression can also be modulated by epigenetic events that do not directly affect E2 DNA binding. Our group recently demonstrated that tandemly integrated repeats of HPV16 DNA could develop into a Brd4-dependent super-enhancer to drive strong expression of the viral oncogenes [15]. Viral genomes are also often integrated in such a way as to disrupt the gene that encodes the E1 replicative helicase, which also disrupts the downstream E2 gene. In HPV infection, the level and nuclear location of the E1 protein are tightly regulated because uncontrolled E1 expression can cause DNA damage and growth arrest [16, 17]. E1 expression can also promote focal genomic instability by inducing overamplification of the integration region [10, 11]. Thus, disruption of the E1 gene could give a selective growth advantage and promote clonal expansion. As mentioned above, most integration events result in expression of a spliced viral—cellular transcript. Jeon and Lambert demonstrated that these fusion transcripts are very often more stable than their viral counterparts, yet again increasing HPV oncogene expression [18]. There are also cases in which an oncogenic HPV has integrated in the vicinity of a cellular oncogene or tumor suppressor gene [2, 19], but this is not thought to be a universal way in which HPV promotes oncogenesis.


The role of integration in oncogenic progression of HPV-associated cancers
Models of integration events that promote oncogenesis.The five integration models shown in Table 1 are shown in the diagram, as indicated to the left. URR (upstream regulatory region), and PE (early promoter), are indicated. The light blue circles in the URR represent E2 binding sites, and the dark blue square is the E1 binding site in the origin of replication (ori).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383336&req=5

ppat.1006211.g002: Models of integration events that promote oncogenesis.The five integration models shown in Table 1 are shown in the diagram, as indicated to the left. URR (upstream regulatory region), and PE (early promoter), are indicated. The light blue circles in the URR represent E2 binding sites, and the dark blue square is the E1 binding site in the origin of replication (ori).
Mentions: Viral genome integration events usually result in dysregulation of E6 and E7 gene expression compared to that expressed from extrachromosomal viral genomes, and this can be achieved in a number of ways (see Fig 2 and Table 1). The earliest model proposed that the integration event disrupts the E2 gene, alleviating E2 transcriptional repression of the E6 and E7 promoter and thus driving oncogene expression [13]. E2 regulation can also be disrupted by methylation of the E2 binding sites in the URR [14]. E6/E7 oncogene expression can also be modulated by epigenetic events that do not directly affect E2 DNA binding. Our group recently demonstrated that tandemly integrated repeats of HPV16 DNA could develop into a Brd4-dependent super-enhancer to drive strong expression of the viral oncogenes [15]. Viral genomes are also often integrated in such a way as to disrupt the gene that encodes the E1 replicative helicase, which also disrupts the downstream E2 gene. In HPV infection, the level and nuclear location of the E1 protein are tightly regulated because uncontrolled E1 expression can cause DNA damage and growth arrest [16, 17]. E1 expression can also promote focal genomic instability by inducing overamplification of the integration region [10, 11]. Thus, disruption of the E1 gene could give a selective growth advantage and promote clonal expansion. As mentioned above, most integration events result in expression of a spliced viral—cellular transcript. Jeon and Lambert demonstrated that these fusion transcripts are very often more stable than their viral counterparts, yet again increasing HPV oncogene expression [18]. There are also cases in which an oncogenic HPV has integrated in the vicinity of a cellular oncogene or tumor suppressor gene [2, 19], but this is not thought to be a universal way in which HPV promotes oncogenesis.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In these cancers, the extrachromosomal viral genome has often become integrated into the host genome... The integration event is thought to drive oncogenesis by dysregulating expression of the E6 and E7 viral oncogenes, leading to inactivation of critical cell cycle checkpoints and increased genetic instability in the host... It is only when these infected cells differentiate and move towards the surface of the epithelium that high levels of viral DNA are synthesized, packaged in virions, and sloughed from the surface of the epithelium in viral-laden squames... HPVs are often found integrated in premalignant lesions and a range of anogenital and oropharyngeal cancers, but this is not part of the viral life cycle... Continued expression of the E1 and E2 replication proteins from integrated genomes causes focal genomic instability at the integration locus, and in most cases, when complete genomes are tandemly integrated, the internal copies are silenced by DNA methylation... Viral genome integration events usually result in dysregulation of E6 and E7 gene expression compared to that expressed from extrachromosomal viral genomes, and this can be achieved in a number of ways (see Fig 2 and Table 1)... E2 regulation can also be disrupted by methylation of the E2 binding sites in the URR... E6/E7 oncogene expression can also be modulated by epigenetic events that do not directly affect E2 DNA binding... Many different methods have been used to detect integrated viral genomes, and more research is needed to clarify the significance of the observed differential rates of integration and to determine whether HPVs promote oncogenesis by different mechanisms at different anatomical locations... Regions of microhomology (1–10 bp) between viral and human genomic sequences are sometimes found at integration breakpoints, as have AT-rich regions of the genome that have the potential to form stem—loop structures that promote the formation of stalled replication forks during replication stress... There are also examples of HPV integration resulting in insertional mutagenesis and/or potential regulatory effects on neighbouring genes... Increased integration within cancer-associated genes or pathways, including the MYC gene locus, have also been reported... However, this is not a universal phenomenon associated with HPV integration... Therefore, many events and processes contribute to the development of an HPV integration event that is a strong driver of oncogenesis; there are likely many dead-end integration events that fail to produce sufficient E6/E7 oncoproteins to drive clonal expansion of the host cell.

No MeSH data available.