Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are human DNA tumor viruses that diverged over 80 million years ago. Each expresses from a single gene a minute amount of the multifunctional products, LANA 1 and EBNA 1, respectively, important for several purposes including maintenance of viral episomes, regulation of viral latency and impairment of cell-cycle checkpoints. The products have a central repeat region that plays a role in the evasion of host immuno surveillance. While classical studies have focused on the products present in the nucleus, recently product from KSHV has been detected in the cytoplasm (156) . The zero frame of the Epstein-Barr virus repeat region contains glycine and alanine, GA, codons and that of KSHV is rich in glutamine and glutamic acid, QE, codons. Although there is limited overall nucleotide sequence similarity between the two viruses, their repeat region sequence is highly similar though offset in terms of respective reading frames by 1 nt. A nested open reading frame in EBNA-1 mRNA encodes a protein capable of inhibiting antigen presentation in cis (157) . An efficient switch, or perhaps multiple switches, to the +1 frame with respect to the genomic sequence, during expression of the EBV sequence yields a product that has ∼35% identity to the product of its KSHV zero frame counterpart (1) . The product of a synthetic EBV construct designed to express what would normally be the +1 frame, inhibits antigen presenetation in cis, consistent with functional relevance of the frameshift derived product which is substantially present in the cytoplasm. Switching to the +1 frame, which also could be by a −2 event, occurs in the expression of the KSHV repeat sequence and it generates a highly repetitive SR-rich peptide with a distinctive subnuclear localization pattern. Whether a switch to the −1 frame, to yield a GA-rich product, also occurs in the expression of KSHV is unknown, and relevant to whether there is any significance to what is the zero frame in the coding sequence. This situation has interesting relevance to the incidental but important frameshifting in the expression of repeat sequences involved in certain human neurodegenerative degenerative disease (see below). The special cases of mutant herpes viruses using frameshifting to counteract therapeutic drugs is also considered below.