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High-risk human papillomavirus infection may develop into a persistent infection that is highly related to the progression of various cancers, including cervical cancer and head and neck squamous cell carcinomas. The most common high-risk subtypes are HPV16 and HPV18. The oncogenic viral proteins expressed by high-risk HPVs E6/E7 are tightly involved in cell proliferation, differentiation, and cancerous transformation since E6/E7 mRNAs are derived from the same pre-mRNA. Hence, the alternative splicing in the E6/E7-coding region affects the balance of the E6/E7 expression level. Interrupting the balance of E6 and E7 levels results in cell apoptosis. Therefore, it is crucial to understand the regulation of E6/E7 splice site selection and the interaction of splicing enhancers and silencers with cellular splicing factors. In this review, we concluded the relationship of different E6/E7 transcripts with cancer progression, the known splicing sites, and the identified cis-regulatory elements within high-risk HPV E6/E7-coding region. Finally, we also reviewed the role of various splicing factors in the regulation of high-risk HPV oncogenic E6/E7 mRNA splicing.

Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular DNA polymerase on the HPV DNA and progeny genomes are synthesized. Following HPV DNA replication, HPV late gene expression is activated. Recent research has shown that the DDR factors also interact with RNA binding proteins and affects RNA processing. DDR factors activated by DNA damage and that associate with HPV DNA can recruit splicing factors and RNA binding proteins to the HPV DNA and induce HPV late gene expression. This induction is the result of altered alternative polyadenylation and splicing of HPV messenger RNA (mRNA). HPV uses the DDR machinery to replicate its DNA genome and to activate HPV late gene expression at the level of RNA processing.

The human papillomavirus type 16 (HPV16) life cycle can be divided into an early stage in which the HPV16 genomic DNA is replicated, and a late stage in which the HPV16 structural proteins are synthesized and virions are produced. A strong coupling between the viral life cycle and the differentiation state of the infected cell is highly characteristic of all HPVs. The switch from the HPV16 early gene expression program to the late requires a promoter switch, a polyadenylation signal switch and a shift in alternative splicing. A number of cis-acting RNA elements on the HPV16 mRNAs and cellular and viral factors interacting with these elements are involved in the control of HPV16 gene expression. This review summarizes our knowledge of HPV16 cis-acting RNA elements and cellular and viral trans-acting factors that regulate HPV16 gene expression at the level of splicing and polyadenylation.

Human papillomavirus 16 (HPV16) 5'-splice site SD226 and 3'-splice site SA409 are required for production of the HPV16 E7 mRNAs, whereas unspliced mRNAs produce E6 mRNAs. The E6 and E7 proteins are essential in the HPV16 replication cycle but are also the major HPV16 proteins required for induction and maintenance of malignancy caused by HPV16 infection. Thus, a balanced expression of unspliced and spliced mRNAs is required for production of sufficient quantities of E6 and E7 proteins under physiological and pathophysiological conditions. If splicing becomes too efficient, the levels of unspliced E6 mRNAs will decrease below a threshold level that is no longer able to produce E6 protein quantities high enough to significantly reduce p53 protein levels. Similarly, if splicing becomes too inefficient, the levels of spliced E7 mRNAs will decrease below a threshold level that is no longer able to produce E7 protein quantities high enough to significantly reduce pRb protein levels. To determine how splicing between SD226 and SA409 is regulated, we have investigated how SA409 is controlled by the cellular proteins hnRNP A1 and hnRNP A2, two proteins that have been shown previously to control HPV16 gene expression. We found that hnRNP A1 and A2 interacted directly and specifically with a C-less RNA element located between HPV16 nucleotide positions 594 and 604 downstream of SA409. Overexpression of hnRNP A1 inhibited SA409 and promoted production of unspliced E6 mRNAs at the expense of the E7 mRNAs, whereas overexpression of hnRNP A2 inhibited SA409 to redirect splicing to SA742, a downstream 3'-splice site that is used for generation of HPV16 E6E7, E1, and E4 mRNAs. Thus, high levels of either hnRNP A1 or hnRNP A2 inhibited production of the promitotic HPV16 E7 protein. We show that the hnRNP A1 and A2 proteins control the relative levels of the HPV16 unspliced and spliced HPV16 E6 and E7 mRNAs and function as inhibitors of HPV16 E7 expression. [ABSTRACT FROM AUTHOR]