The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription

Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell host & microbe (Impact Factor: 12.19). 03/2010; 7(3):234-44. DOI: 10.1016/j.chom.2010.02.005
Source: PubMed

ABSTRACT The Tat protein of HIV-1 plays an essential role in HIV gene expression by promoting efficient elongation of viral transcripts. Posttranslational modifications of Tat fine-tune interactions of Tat with cellular cofactors and TAR RNA, a stem-loop structure at the 5' ends of viral transcripts. Here, we identify the lysine methyltransferase Set7/9 (KMT7) as a coactivator of HIV transcription. Set7/9-KMT7 associates with the HIV promoter in vivo and monomethylates lysine 51, a highly conserved residue located in the RNA-binding domain of Tat. Knockdown of Set7/9-KMT7 suppresses Tat transactivation of the HIV promoter, but does not affect the transcriptional activity of methylation-deficient Tat (K51A). Set7/9-KMT7 binds TAR RNA by itself and in complex with Tat and the positive transcription elongation factor P-TEFb. Our findings uncover a positive role for Set7/9-KMT7 and Tat methylation during early steps of the Tat transactivation cycle.

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Available from: Sara Pagans, Aug 21, 2015
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    • "Epigenetic regulation of gene expression, including mechanisms dependent on histone methylation, have been implicated in a variety of diseases including cancer (Albert and Helin, 2010; Kelly et al., 2010; Nimura et al., 2010; Vallance and Leiper, 2004; Yoshimatsu et al., 2011). Protein lysine (PKMT) and protein arginine (PRMT) methyltransferases catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to lysine or arginine residues on histone tails, respectively, and in many cases also methylate non-histone proteins (Dhayalan et al., 2011; Huang et al., 2010; Liu et al., 2011; Pagans et al., 2010; Shi et al., 2007). These two families of proteins are distinguishable by the primary sequence of their catalytic domains and three-dimensional structures (Campagna-Slater et al., 2011; Copeland et al., 2009). "
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    • "Extrapolation of this structure to HIV-1 Tat indicates that Lys51 plays a central role in the interaction with bases of the first Watson-Crick base pairings proximal to the hairpin loop of TAR RNA. Di-or trimethylation of this residue may interfere with this interaction, while monomethylation strengthens the complex formation between Tat, TAR and CycT1 (Pagans et al., 2010). Interestingly, Set7/9 itself possesses weak TAR RNA binding activity that requires both bulge and loop structures in TAR. "
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