![]() ![]() ![]() Low levels of papillomavirus E2 protein stimulate transcription from the HPV early promoter, whereas high levels of E2, shut down the early promoter and E6 and E7 expression ( 10–12). Apart from its role as a DNA replication factor, HPV E2 is also a transcriptional regulator of the HPV early genes, including the E6 and E7 oncogenes ( 10–12, 15–18). The HPV replication and transcription factor E2 plays a key role in this switch as it downregulates the HPV early promoter and inhibits the HPV early polyadenylation signal to induce HPV late gene expression ( 14). This switch includes a promoter switch, a polyA site switch and a shift in HPV alternative mRNA splicing ( 13). ![]() As cell differentiation proceeds, a switch from the HPV early to the late gene expression program is induced ( 3, 4). Simultaneous expression of the two HPV DNA replication factors E1 and E2 ensures replication of the HPV DNA genome ( 9–12). Essential early proteins include E6 and E7 that prevent apoptosis and induce proliferation of the HPV-infected cell ( 7, 8). The life-cycle of HPV is strictly linked to cell differentiation in the squamous epithelium with expression of the HPV early genes in the lower and middle layers of the stratified epithelium ( 3–6). HPV16 is the most common high risk HPV types and is associated with various anogenital cancers as well as head and neck cancer ( 1, 2). Intriguingly, hnRNP G also promoted intron retention of the HPV16 E6 coding region thereby inhibiting production of spliced E7 oncogene mRNAs.Ī subset of the human papillomaviruses (HPV) with tropism for mucosal epithelial cells can establish persistent infections that may progress to cancer ( 1). The DDR reduced sumoylation of hnRNP G and pharmacological inhibition of sumoylation enhanced HPV16 E2 mRNA splicing and interactions between hnRNP G and E2 mRNAs and U2AF65. ![]() The interactions between hnRNP G and HPV16 E2 mRNAs and U2AF65 increased in response to keratinocyte differentiation as well as by the induction of the DNA damage response (DDR). The splicing-enhancing function of hnRNP G mapped to amino acids 236–286 of hnRNP G that were also shown to interact with splicing factor U2AF65. The splicing enhancer sequence interacted with cellular RNA binding protein hnRNP G that promoted splicing to SA2709 and enhanced E2 mRNA production. Mutational inactivation of the splicing enhancer reduced splicing to E2-mRNA specific splice site SA2709 and resulted in increased levels of unspliced E1-encoding mRNAs. This uridine-less splicing enhancer sequence (ACGAGGACGAGGACAAGGA) contains 84% adenosine and guanosine and 16% cytosine and consists of three ‘AC(A/G)AGG’-repeats. We have investigated how HPV16 E2 expression is regulated and have identifed a splicing enhancer that is required for production of HPV16 E2 mRNAs. Human papillomavirus type 16 (HPV16) E2 is an essential HPV16 protein. ![]()
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