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Transcription.jpg

Transcriptional Elongation

The lab has a longstanding interest in the role of factor acetylation in cells. We identified the HIV transactivator Tat as a target for the cellular histone acetyltransferase p300/CBP in 1999, when only one other protein, the cellular p53 protein, was shown to be regulated by reversible acetylation. We have since demonstrated that Tat acetylation is reversed by the NAD+ deacetylase SIRT1 and that the acetylated residue in Tat provides a unique interface with the bromodomain of the PCAF acetyltransferase. This is relevant for current efforts to reverse HIV latency with HDAC inhibitors or compounds disrupting interactions of acetylated proteins with bromodomain proteins—most notably BET inhibitors. Current and future efforts are focused on a comprehensive analysis of Tat posttranslational modifications as therapeutic targets to modulate HIV transcription, as well as the role of reversible acetylation of the RNA polymerase II C-terminal domain (CTD) recently identified by us as a modification uniquely linked to the regulation of polymerase pausing.  

 

HIV Transcription

Selected Publications:

Schröder S, Herker E, Itzen F, He D, Thomas S, Gilchrist DA, Kaehlcke K, Cho S, Pollard KS, Capra JA, Schnolzer M, Cole PA, Geyer M, Bruneau BG, Adelman K, Ott M (2013) Acetylation of RNA Polymerase II Regulates Growth-Factor-Induced Gene Transcription in Mammalian Cells. Mol Cell 52:314–324.

Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L, Aull K, Li P-C, Planelles V, Bradner JE, Zhou M-M, Siliciano RF, Weinberger L, Verdin E, Ott M (2013) BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 12:452–462.

Ott M, Geyer M, Zhou Q (2011) The Control of HIV Transcription: Keeping RNA Polymerase II on Track. Cell Host Microbe 10:426–435. 

Sakane N, Kwon H-S, Pagans S, Kaehlcke K, Mizusawa Y, Kamada M, Lassen KG, Chan J, Greene WC, Schnoelzer M, Ott M (2011) Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog 7:e1002184. 

Pagans S, Kauder SE, Kaehlcke K, Sakane N, Schroeder S, Dormeyer W, Trievel RC, Verdin E, Schnolzer M, Ott M (2010) The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA, monomethylates the viral transactivator Tat, and enhances HIV transcription. Cell Host Microbe 7:234–244. 

Cho S, Schroeder S, Kaehlcke K, Kwon H-S, Pedal A, Herker E, Schnoelzer M, Ott M (2009) Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J 28:1407–1417.

Dorr A, Kiermer V, Pedal A, Rackwitz H-R, Henklein P, Schubert U, Zhou M-M, Verdin E, Ott M (2002) Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J 21:2715–2723.

Ott M, Schnolzer M, Garnica J, Fischle W, Emiliani S (1999) Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. Curr Biol 9:1489-92.