Cellular mRNA activates transcription elongation by displacing 7SK RNA.
The positive transcription elongation factor P-TEFb is a pivotal regulator of gene expression in higher cells. Originally identified in Drosophila, attention was drawn to human P-TEFb by the discovery of its role as an essential cofactor for HIV-1 transcription. It is recruited to HIV transcription complexes by the viral transactivator Tat, and to cellular transcription complexes by a plethora of transcription factors. P-TEFb activity is negatively regulated by sequestration in a complex with the HEXIM proteins and 7SK RNA. The mechanism of P-TEFb release from the inhibitory complex is not known. We report that P-TEFb-dependent transcription from the HIV promoter can be stimulated by the mRNA encoding HIC, the human I-mfa domain-containing protein. The 3'-untranslated region of HIC mRNA is necessary and sufficient for this action. It forms complexes with P-TEFb and displaces 7SK RNA from the inhibitory complex in cells and cell extracts. A 314-nucleotide sequence near the 3' end of HIC mRNA has full activity and contains a predicted structure resembling the 3'-terminal hairpin of 7SK that is critical for P-TEFb binding. This represents the first example of a cellular mRNA that can regulate transcription via P-TEFb. Our findings offer a rationale for 7SK being an RNA transcriptional regulator and suggest a practical means for enhancing gene expression.
Young
Tara M
TM
Department of Biochemistry and Molecular Biology, New Jersey Medical School, Newark, New Jersey, United States of America.
Tsai
Michael
M
Tian
Bin
B
Mathews
Michael B
MB
Pe'ery
Tsafi
T
D020413:3' Untranslated Regions; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000378:metabolism; D005786:Gene Expression Regulation; D006678:HIV / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D018076:DNA, Complementary; D012333:RNA, Messenger; D042925:Positive Transcriptional Elongation Factor B