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    Hexim proteins are RNA-dependent regulators whose main target is 7SK long non-coding RNA, a major regulator of eukaryotic mRNA transcription. 7SK RNPs control available intracellular concentrations of the kinase P-TEFb (Cdk9-CyclinT1/2) by sequestering it in an inactive form. Active P-TEFb phosphorylates NELF, DSIF, and the RNA polymerase II CTD to transition it from promoter-proximal pausing to productive elongation. P-TEFb associates with 7SK RNP via Hexim, which directly binds 7SK RNA. However, free Hexim is in an autoinhibited state that cannot inactivate P-TEFb, and how Hexim autoinhibition is released by 7SK remains unknown. Here, we show that one Hexim1 homodimer binds two sites on linear 7SK RNA in a manner that exposes the Cdk9 binding sites, which are otherwise masked within the autoinhibited dimer. These results provide mechanistic insights into Hexim-RNA specificity and explain how P-TEFb can be effectively regulated to respond to changing levels of transcriptional signaling.

    Citation

    Yuan Yang, Maria Grazia Murrali, Yaqiang Wang, Sabrina Galvan, Neha Ajjampore, Juli Feigon. HEXIM1 homodimer binds two sites on 7SK RNA to release autoinhibition for P-TEFb inactivation. bioRxiv : the preprint server for biology. 2024 Oct 13


    PMID: 39416148

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