The small nuclear 7SK RNA negatively controls transcription by inactivating positive transcription elongation factor b (P-TEFb) 1,2. Recent studies have shown that 7SK RNA as an inhibitor of P-TEFb is one of the main targets of the HIV-1 viral gene products to switch from inefficient to efficient viral transcription 3,4.
We have recently shown that 7SK RNA also directly controls HMGA1 transcription activity 5,6. HMGA1 is a master regulator of gene expression and its deregulation is associated with virtually any type of human cancer 7,8,9,10. The degree of HMGA1 over-expression thereby correlates with tumor malignancy and metastatic potential. 7SK snRNA directly interacts through its loop 2 (7SK L2) with the first A/T DNA binding hook of HMGA1. We have developed several 7SK L2 RNA chimera with the Epstein Barr Virus expressed RNA 2 (EBER2) to target HMGA1 function in transcription regulation. The efficiency of interfering with HMGA1 transcription activity by the chimeric 7SK L2 — EBER2 fusions by large exceeds the efficiency of 7SK wild-type RNA due to the stronger EBER2 promoter activity. Furthermore, the 7SK L2 — EBER2 chimeras do not interfere with P-TEFb controlled transcription elongation or the formation of 7SK sn/hnRNPs.
These findings raise important questions about the regulation of RNA Polymerase III transcription as well as mechanisms which control 7SK RNA activity. The recent findings not only shed light on RNA-mediated regulatory pathways, but may also help to understand and potentially find new therapeutic approaches to efficiently fight oncogenesis and HIV.
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