Multiple tandemly repeated binding sites for the YY1 repressor and transcription factors AP-1 and SP-1 are clustered within intron-1 of the gene encoding the IE110 transactivator of herpes simplex virus Type 1

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Abstract
Expression of the IE110 (ICP0) transactivator protein of HSV appears to be critical for reactivation from the latent state and occurs at immediate-early times during the lytic cycle under the control of an upstream divergent enhancer-promoter region that contains multiple Oct and Sp-1 binding sites overlapping with VP16 response elements. Surprisingly, the large 800-bp first intron of the HSV-1 IE110 gene also proved to have a complex repetitive organization encompassing multiple transcription factor binding sites within four distinct domains. DNase I footprinting studies revealed that 13 of 17 copies of a 15-bp repeated element represented high-affinity binding sites for the cellular YY1 repressor protein. Between 4 and 7 of these sites are direct tandem repeats and the rest are interspersed with three repeated AT-rich motifs and a dyad symmetry region containing two strong AP-1 binding sites and an adjacent SP-1 binding site on each arm. Several of the YY1 sites also bound weakly to SRF. The intron also contains four clustered purine/pyrimidine tracts of between 16 and 23 bp long. Both the AP-1/AP-2/SP-1 dyad protein binding region and, to a lesser extent, the YY1 tandem-repeat cluster conferred responsiveness to TPA when placed upstream of a heterologous promoter in transient expression assays. The functional significance of the HSV-1 IE110 intron region is unknown as yet, but the novel arrangement of tandemly repeated YY1 sites has the potential to produce structural bending and transcriptional attenuation effects. Interestingly, few of these transcription factor binding motifs are conserved in the equivalent IE110 intron of HSV-2, and the domain appears to represent a unique alternative control region that is specific for HSV-1.