Human papillomavirus regulation of SR proteins

Splicing is a cellular process essential for mRNA biogenesis. There are two types of splicing: constitutive and alternative splicing. During constitutive splicing, non-coding intron sequences are removed and exonic coding sequences are spliced together to form mature mRNAs. Alternative splicing can maximize the coding capacity of the genome by specific alternative selection of exons from multi-exon metazoan pre-mRNAs. Splicing is a tightly regulated process, so when control is lost disease may occur. SR proteins (serine/arginine-rich proteins) are a family of highly conserved splicing regulators that are also involved in other steps in RNA biogenesis and expression. Many viruses have evolved to utilize the cellular splicing machinery to enhance their proteome from a limited number of genes. HPV (human papillomavirus) is an example of one such virus. The HPV transcription/replication factor E2 (early 2) specifically up-regulates expression of the SR proteins SF2/ASF (splicing factor 2/alternative splicing factor), SRp20 and SC35 in infected epithelial cells. These SR proteins are essential for viral RNA processing. SF2/ASF is a proto-oncogene that is also up-regulated in a number of cancers. For example, SF2/ASF, together with SRp20 and SC35 is selectively up-regulated in cervical tumours caused by persistent oncogenic HPV infection. However, the mode of SR protein up-regulation in tumours is different to the E2-directed transcriptional regulation in normal transient HPV infection. SR proteins could provide excellent targets for HPV antiviral therapy as well as anticancer therapy.