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Review
. 2003 May-Jun;13(3):173-84.
doi: 10.1002/rmv.387.

Split genes and their expression in Kaposi's sarcoma-associated herpesvirus

Zhi-Ming Zheng  1
Affiliations
Review

Split genes and their expression in Kaposi's sarcoma-associated herpesvirus

Zhi-Ming Zheng. Rev Med Virol. 2003 May-Jun.

Abstract

A split or interrupted gene is defined as a gene consisting of introns and exons. Removal (splicing) of the intron(s) from a primary transcript (pre-mRNA) is essential for creating a mRNA. Initial assignment of a potential protein coding region in the KSHV genome was based on the initiation codon context and predicted protein size larger than 100 amino acids, but the gene discontinuity was disregarded. Experimental investigation of the assigned ORFs has demonstrated that there are up to 25 split genes, more than one fourth of the total KSHV genes described in the KSHV genome. This includes the genes involved in all phases (latent, immediate early, early and late) of KSHV infection. The complexity of a split gene expression depends upon the availability of a proximal promoter and polyadenylation (pA) signal. Sharing a single promoter or a single pA signal by two or three genes is not uncommon in the expression of KSHV split genes and the resulting transcripts are usually polycistronic. Among those of KSHV split genes, 15 genes express a bicistronic or tricistronic RNA and 10 genes express a monocistronic RNA. Alternative RNA splicing could happen in a particular pre-mRNA due to intron or exon inclusion or skipping or the presence of an alternative 5' splice site or 3' splice site. This may, respectively, result in at least 8 species of K8 and 14 species of K15 transcripts. This appears to be related to cell differentiation and stages of the virus infection, presumably involving viral cis elements and trans splicing factors.

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Figures

FIG. 1
FIG. 1
The ORF50 (immediately early), K8 (early), and K8.1 (late) transcripts are initiated from alternative promoters but share a common pA site at nt 76714, and produce an array of spliced and unspliced transcripts (36–38, 49). Because of alternative splicing, a total of approximately 19 RNA species (A to S) are predicted from three pre-mRNAs: tricistronic ORF50/K8/K8.1, bicistronic K8/K8.1, and monocistronic K8.1. Splicing of these pre-mRNAs often results in inclusion of the intron at nt 75563 to nt 75645 (RNAs C, E, G, K, M and O) due to suboptimal features of the splice sites. Among those transcripts, RNA D encodes for Rta, RNA L encodes for K-bZip and RNA R encodes for K8.1A in lytic infection.
FIG. 2
FIG. 2
Alternative splicing and polyadenylation of ORF 73/72/K13 transcripts initiated from a single promoter, P127880 (44, 46). The coding direction of these genes is backward because they are transcribed from the opposite strand. The presence of an alternative 3′ ss in exon 2 and an alternative non-canonical pA signal (AGUAAA) at nt 124061 leads to the production of a 1.7 kb bicistronic RNA (RNA B, alternative 3′ ss selection) and a 3.3 kb monocistronic RNA (RNA C, alternative polyadenylation) (Canham, M & Talbot, SJ., personal communication). Tricistronic RNA A (ORF73/72/K13) is mainly expressed in lymph node cells and bicistronic RNA B (ORF72/K13) is most common in late-stage KS lesions (70% spindle cells) (58).
FIG. 3
FIG. 3
Extensive exon and intron skipping and alternative splicing of K15 pre-mRNA (24,25). A dashed vertical line on exon 1 and 3 of each RNA species represents a possible alternative 5′ ss. The depiction also shows a potential K15 promoter P136854 (TATATAA) and a putative K15 pA site at nt 130512 downstream of ORF75 (43). K15 is latently expressed in KSHV-positive PEL cell lines and plasmablasts in MCD (55).
FIG. 4
FIG. 4
Regulation of splice site selection by cis elements and trans splicing factors and possible involvement of KSHV gene products. Diagram shows a pre-mRNA containing three exons (open boxes) and two introns (lines). Two categories of splicing regulatory elements, splicing enhancers and splicing suppressors (silencers), have been described recently in the exons (grey boxes) or introns (small black boxes) of several viral and mammalian pre-mRNA substrates (94–99). The heavy- and light-grey boxes in exon 2 are, respectively, exonic splicing enhancers (ESE) and exonic splicing suppressor (ESS) which are often juxtaposed. The small black boxes in the introns are either intronic splicing enhancers (ISE) or intronic splicing suppressors (ISS). Through interacting with SR and other SR related splicing factors, these regulatory elements positively (+) or negatively (−) control the selection of a splice site upstream or downstream. An internal exon is also usually defined as less than 500 nts in size (51). RNA 5′ capping (100, 101) and 3′ polyadenylation (102, 103) couple with RNA splicing to promote recognition of terminal splice sites. Negative effects of KSHV ORF57 and PAN RNA on RNA splicing are hypothetical.
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