RNA Binding Proteins that Control Human Papillomavirus Gene Expression

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.

Figure 1

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.

Figure 2

Sequences of cis-acting RNA elements on the HPV1 or HPV16 genome. Binding sites for cellular factors are capitalized and in red. See text for details. (A) Splicing silencer downstream of SA5639. (B) Splicing enhancer downstream of SA5639. (C) The AU-rich RNA element in the HPV1 late UTR. (D) The U-rich region of the HPV16 early UTR. (E) HPV16 splicing silencer element upstream of SD3632. (F) The polyadenylation enhancer downstream of HPV16 pAE. (G) HPV16 splicing enhancer downstream of SA3358. (H) HPV16 splicing regulatory element at SA3358. (I) The negative regulatory element in the HPV16 late UTR.