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RNA Binding Proteins that Control Human Papillomavirus Gene Expression.

Kajitani N, Schwartz S - Biomolecules (2015)

Bottom Line: These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV.Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer.Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Lund University, Lund 22184, Sweden. Naoko.Kajitani@med.lu.se.

ABSTRACT
The human papillomavirus (HPV) life cycle is strictly linked to the differentiation program of the infected mucosal epithelial cell. In the basal and lower levels of the epithelium, early genes coding for pro-mitotic proteins and viral replication factors are expressed, while terminal cell differentiation is required for activation of late gene expression and production of viral particles at the very top of the epithelium. Such productive infections are normally cleared within 18-24 months. In rare cases, the HPV infection is stuck in the early stage of the infection. Such infections may give rise to cervical lesions that can progress to cancer, primarily cancer of the uterine cervix. Since cancer progression is strictly linked to HPV gene expression, it is of interest to understand how HPV gene expression is regulated. Cis-acting HPV RNA elements and cellular RNA-binding proteins control HPV mRNA splicing and polyadenylation. These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV. Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer. Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression.

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Related in: MedlinePlus

Schematic representation of the HPV16 genome. Boxes indicate open reading frames. HPV16 early and late promoters p97 and p670, respectively, early and late polyadenylation signals pAE and pAL, respectively, and 5'- (SD) and 3'- (SA) splice sites are indicated. A subset of HPV16 mRNAs initiating at the p670 promoter is shown and splicing regulatory elements are indicated. Filled boxes represent positive RNA elements that enhance usage of splice sites or polyA signals and white boxes represent suppressive RNA elements that inhibit splice sites or polyA sites. Examples of alternatively spliced HPV16 mRNAs initiated at early (p97) and late (p670) promoters and terminated at early (pAE) or late (pAL) polyadenylation signals are displayed.
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biomolecules-05-00758-f001: Schematic representation of the HPV16 genome. Boxes indicate open reading frames. HPV16 early and late promoters p97 and p670, respectively, early and late polyadenylation signals pAE and pAL, respectively, and 5'- (SD) and 3'- (SA) splice sites are indicated. A subset of HPV16 mRNAs initiating at the p670 promoter is shown and splicing regulatory elements are indicated. Filled boxes represent positive RNA elements that enhance usage of splice sites or polyA signals and white boxes represent suppressive RNA elements that inhibit splice sites or polyA sites. Examples of alternatively spliced HPV16 mRNAs initiated at early (p97) and late (p670) promoters and terminated at early (pAE) or late (pAL) polyadenylation signals are displayed.

Mentions: The HPV virion is approximately 50 nm in diameter and consists of eight kilobases, double stranded, circular DNA genome embedded in an icosahedral capsid formed by the HPV L1 and L2 capsid proteins [7]. The viral genome contains a non-coding region (NCR) located between the end of the late L1 coding region and the beginning of the early E6 coding region (Figure 1). It encodes an origin of DNA replication, binding sites for the HPV E2 replication- and transcription-factor and the HPV early promoter. In HPV16, the early promoter is termed p97 and could potentially be used to express viral mRNAs encoding all HPV proteins. However, HPV mRNAs are either polyadenylated at the early polyadenylation signal (pAE), located downstream of the early genes (E1, E2, E4–E7), or at the late polyadenylation signal (pAL) located downstream of the late genes L1 and L2 [8,9]. At the early stage in the viral life cycle, mRNAs are transcribed from the early promoter p97 and polyadenylated at pAE, while at the late stage the late promoter p670 located in the E7 coding region is activated (Figure 1) [7,10,11]. Initiation at p670 excludes transcription of the E6 and E7 genes, but produces “early” mRNAs encoding E1, E2, E4, E5 that are polyadenylated at pAE, and late mRNAs encoding L1 and L2 that are polyadenylated at the late polyadenylation signal pAL. The relative levels of the individual HPV mRNAs are determined by alternative splicing and polyadenylation (Figure 1) [9,12,13]. Therefore, there is a switch from the early stage of the viral life cycle in which all early genes are expressed, to the late stage in which all early genes but E6 and E7 are expressed as well as the two late structural proteins L1 and L2. The switch from early to late HPV gene expression is dependent on cell differentiation. HPV L1 and L2 late gene expression is required for virus production and normally occurs in terminally differentiated cells at the very top of the epithelium.


RNA Binding Proteins that Control Human Papillomavirus Gene Expression.

Kajitani N, Schwartz S - Biomolecules (2015)

Schematic representation of the HPV16 genome. Boxes indicate open reading frames. HPV16 early and late promoters p97 and p670, respectively, early and late polyadenylation signals pAE and pAL, respectively, and 5'- (SD) and 3'- (SA) splice sites are indicated. A subset of HPV16 mRNAs initiating at the p670 promoter is shown and splicing regulatory elements are indicated. Filled boxes represent positive RNA elements that enhance usage of splice sites or polyA signals and white boxes represent suppressive RNA elements that inhibit splice sites or polyA sites. Examples of alternatively spliced HPV16 mRNAs initiated at early (p97) and late (p670) promoters and terminated at early (pAE) or late (pAL) polyadenylation signals are displayed.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496695&req=5

biomolecules-05-00758-f001: Schematic representation of the HPV16 genome. Boxes indicate open reading frames. HPV16 early and late promoters p97 and p670, respectively, early and late polyadenylation signals pAE and pAL, respectively, and 5'- (SD) and 3'- (SA) splice sites are indicated. A subset of HPV16 mRNAs initiating at the p670 promoter is shown and splicing regulatory elements are indicated. Filled boxes represent positive RNA elements that enhance usage of splice sites or polyA signals and white boxes represent suppressive RNA elements that inhibit splice sites or polyA sites. Examples of alternatively spliced HPV16 mRNAs initiated at early (p97) and late (p670) promoters and terminated at early (pAE) or late (pAL) polyadenylation signals are displayed.
Mentions: The HPV virion is approximately 50 nm in diameter and consists of eight kilobases, double stranded, circular DNA genome embedded in an icosahedral capsid formed by the HPV L1 and L2 capsid proteins [7]. The viral genome contains a non-coding region (NCR) located between the end of the late L1 coding region and the beginning of the early E6 coding region (Figure 1). It encodes an origin of DNA replication, binding sites for the HPV E2 replication- and transcription-factor and the HPV early promoter. In HPV16, the early promoter is termed p97 and could potentially be used to express viral mRNAs encoding all HPV proteins. However, HPV mRNAs are either polyadenylated at the early polyadenylation signal (pAE), located downstream of the early genes (E1, E2, E4–E7), or at the late polyadenylation signal (pAL) located downstream of the late genes L1 and L2 [8,9]. At the early stage in the viral life cycle, mRNAs are transcribed from the early promoter p97 and polyadenylated at pAE, while at the late stage the late promoter p670 located in the E7 coding region is activated (Figure 1) [7,10,11]. Initiation at p670 excludes transcription of the E6 and E7 genes, but produces “early” mRNAs encoding E1, E2, E4, E5 that are polyadenylated at pAE, and late mRNAs encoding L1 and L2 that are polyadenylated at the late polyadenylation signal pAL. The relative levels of the individual HPV mRNAs are determined by alternative splicing and polyadenylation (Figure 1) [9,12,13]. Therefore, there is a switch from the early stage of the viral life cycle in which all early genes are expressed, to the late stage in which all early genes but E6 and E7 are expressed as well as the two late structural proteins L1 and L2. The switch from early to late HPV gene expression is dependent on cell differentiation. HPV L1 and L2 late gene expression is required for virus production and normally occurs in terminally differentiated cells at the very top of the epithelium.

Bottom Line: These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV.Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer.Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Lund University, Lund 22184, Sweden. Naoko.Kajitani@med.lu.se.

ABSTRACT
The human papillomavirus (HPV) life cycle is strictly linked to the differentiation program of the infected mucosal epithelial cell. In the basal and lower levels of the epithelium, early genes coding for pro-mitotic proteins and viral replication factors are expressed, while terminal cell differentiation is required for activation of late gene expression and production of viral particles at the very top of the epithelium. Such productive infections are normally cleared within 18-24 months. In rare cases, the HPV infection is stuck in the early stage of the infection. Such infections may give rise to cervical lesions that can progress to cancer, primarily cancer of the uterine cervix. Since cancer progression is strictly linked to HPV gene expression, it is of interest to understand how HPV gene expression is regulated. Cis-acting HPV RNA elements and cellular RNA-binding proteins control HPV mRNA splicing and polyadenylation. These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV. Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer. Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression.

Show MeSH
Related in: MedlinePlus