Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors

Mutations in the clk-1 gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan in Caenorhabditis elegans. We demonstrate here that this life extension is linked to the repression of cytoplasmic mRNA translation, independent of the alleged nuclear form of CLK-1. Clk-1 mutations inhibit polyribosome formation similarly to daf-2 mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs in clk-1(qm30) mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TATA-binding protein-associated factor 4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates the clk-1 inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein synthesis in eukaryotic lifespan extension and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TATA-binding protein-associated factor 4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

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Transcription Factor IIA Derepresses TATA-binding Protein (TBP)-associated Factor Inhibition of TBP-DNA Binding

Journal of Biological Chemistry ◽

10.1074/jbc.273.23.14293 ◽

1998 ◽

Vol 273 (23) ◽

pp. 14293-14300 ◽

Cited By ~ 42

Author(s):

Josef Ozer ◽

Katherine Mitsouras ◽

Dennis Zerby ◽

Michael Carey ◽

Paul M. Lieberman

Keyword(s):

Transcription Factor ◽

Dna Binding ◽

Binding Protein ◽

Tata Binding Protein ◽

Associated Factor

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Regulation of rRNA Synthesis by TATA-Binding Protein-Associated Factor Mot1

Molecular and Cellular Biology ◽

10.1128/mcb.00054-07 ◽

2007 ◽

Vol 27 (8) ◽

pp. 2886-2896 ◽

Cited By ~ 9

Author(s):

Arindam Dasgupta ◽

Rebekka O. Sprouse ◽

Sarah French ◽

Pavel Aprikian ◽

Robert Hontz ◽

...

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Binding Protein ◽

Tata Binding Protein ◽

Rrna Synthesis ◽

Direct Role ◽

Pol Ii ◽

Associated Factor ◽

Pol I

ABSTRACT Mot1 is an essential, conserved, TATA-binding protein (TBP)-associated factor in Saccharomyces cerevisiae with well-established roles in the global control of RNA polymerase II (Pol II) transcription. Previous results have suggested that Mot1 functions exclusively in Pol II transcription, but here we report a novel role for Mot1 in regulating transcription by RNA polymerase I (Pol I). In vivo, Mot1 is associated with the ribosomal DNA, and loss of Mot1 results in decreased rRNA synthesis. Consistent with a direct role for Mot1 in Pol I transcription, Mot1 also associates with the Pol I promoter in vitro in a reaction that depends on components of the Pol I general transcription machinery. Remarkably, in addition to Mot1's role in initiation, rRNA processing is delayed in mot1 cells. Taken together, these results support a model in which Mot1 affects the rate and efficiency of rRNA synthesis by both direct and indirect mechanisms, with resulting effects on transcription activation and the coupling of rRNA synthesis to processing.

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