Article

Molecular basis of RNA polymerase III transcription repression by Maf1.

Gene Center and Department of Biochemistry, Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Cell (Impact Factor: 31.96). 10/2010; 143(1):59-70. DOI: 10.1016/j.cell.2010.09.002
Source: PubMed

ABSTRACT RNA polymerase III (Pol III) transcribes short RNAs required for cell growth. Under stress conditions, the conserved protein Maf1 rapidly represses Pol III transcription. We report the crystal structure of Maf1 and cryo-electron microscopic structures of Pol III, an active Pol III-DNA-RNA complex, and a repressive Pol III-Maf1 complex. Binding of DNA and RNA causes ordering of the Pol III-specific subcomplex C82/34/31 that is required for transcription initiation. Maf1 binds the Pol III clamp and rearranges C82/34/31 at the rim of the active center cleft. This impairs recruitment of Pol III to a complex of promoter DNA with the initiation factors Brf1 and TBP and thus prevents closed complex formation. Maf1 does however not impair binding of a DNA-RNA scaffold and RNA synthesis. These results explain how Maf1 specifically represses transcription initiation from Pol III promoters and indicate that Maf1 also prevents reinitiation by binding Pol III during transcription elongation.

0 Bookmarks
 · 
132 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mechanistic target of rapamycin complex 1 (mTORC1) is a well-known regulator of cell growth and proliferation in response to environmental stimuli and stressors. To date, the majority of mTORC1 studies have focused on its function as a cytoplasmic effector of translation regulation. However, recent studies have identified additional, nuclear-specific roles for mTORC1 signaling related to transcription of the ribosomal DNA (rDNA) and ribosomal protein (RP) genes, mitotic cell cycle control, and the regulation of epigenetic processes. As this area of study is still in its infancy, the purpose of this review to highlight these significant findings and discuss the relevance of nuclear mTORC1 signaling dysregulation as it pertains to health and disease.
    Cell cycle (Georgetown, Tex.) 02/2014; 13(5). · 5.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transcriptional regulation is one of the most important steps in control of cell identity, growth, differentiation, and development. Many signaling pathways controlling these processes ultimately target the core transcription machinery that, for protein coding genes, consists of RNA polymerase II (Pol II) and the general transcription factors (GTFs). New studies on the structure and mechanism of the core assembly and how it interfaces with promoter DNA and coactivator complexes have given tremendous insight into early steps in the initiation process, genome-wide binding, and mechanisms conserved for all nuclear and archaeal Pols. Here, we review recent developments in dissecting the architecture of the Pol II core machinery with a focus on early and regulated steps in transcription initiation.
    Trends in Biochemical Sciences 10/2013; · 13.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The regulatory mechanisms by which hydrogen peroxide (H2O2) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed. The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians. Multiple H2O2 sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm-nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes. We also discuss how H2O2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H2O2, being activated by different concentrations and times of exposure to H2O2. The specific regulation of local H2O2 concentrations is also crucial and results from H2O2 localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H2O2 reactivity with sensor molecules. Rate constants of 140 M(-1) s(-1) and ≥1.3 × 10(3) M(-1) s(-1) were estimated, respectively, for the reaction of H2O2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H2O2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.
    Redox biology. 01/2014; 2:535-562.

Full-text (2 Sources)

View
36 Downloads
Available from
May 21, 2014