Kaposi's sarcoma-associated herpesvirus (KSHV) replication and transcription activator (RTA) is well established as a key transcriptional activator that regulates the KSHV life cycle from latency to lytic replication. It is expressed immediately after infection and activates a number of viral genes leading to virus replication. The RTA-responsive element (RRE) in the RTA target gene promoters is critical for RTA to mediate this transactivation. A number of non-conserved RREs have been identified in various RTA-responsive promoters, and AT-rich sequences have been proposed to serve as RTA targets, but no consensus RRE sequence has been identified so far. Two non-conserved RREs (RRE1 and RRE2) containing AT-rich sequences have been identified previously in the promoter of one of the KSHV lytic genes, ORF57, which can be strongly activated by RTA. Based on homology with the consensus sequence of the Epstein-Barr virus Rta RRE, this study identified a third RTA-responsive element (RRE3) in the ORF57 promoter. This RRE comprised a GC-rich sequence that could bind RTA both in vitro and in vivo, and plays a role in RTA-mediated transactivation of the ORF57 promoter. The presence of two of the three RREs in close proximity to each other was required for optimal RTA-mediated transactivation of the ORF57 promoter, even though the presence of only one RRE is needed for RTA binding. These results suggest that the ability of RTA to mediate transcriptional activation is distinct from its ability to bind to its target elements.
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