Control of transcription by Pontin and Reptin

Zoologisches Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Trends in cell biology (Impact Factor: 12.01). 05/2007; 17(4):187-92. DOI: 10.1016/j.tcb.2007.02.005
Source: PubMed


Pontin and Reptin are two closely related members of the AAA+ family of DNA helicases. They have roles in diverse cellular processes, including the response to DNA double-strand breaks and the control of gene expression. The two proteins share residence in different multiprotein complexes, such as the Tip60, Ino80, SRCAP and Uri1 complexes in animals, which are involved (directly or indirectly) in transcriptional regulation, but they also function independently from each other. Both Reptin and Pontin repress certain transcriptional targets of Myc, but only Reptin is required for the repression of specific beta-catenin and nuclear factor-kappaB targets. Here, I review recent studies that have addressed the mechanisms of transcriptional control by Pontin and Reptin.

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Available from: Peter Gallant, Sep 30, 2015
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    • "Published data suggest that their main function may be assembly or activation of the complexes in which they are contained. This theory supports the fact, that the protein level of Rvb1 and Rvb2 in yeasts is low compared to the abundance of the complexes in which they are involved and therefore only associate with these complexes transiently (Gallant, 2007; Nano and Houry, 2013). RPAP3 and PIH1D1 are subunits specific exclusively for the R2TP complex. "
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    ABSTRACT: The R2TP complex is a HSP90 co-chaperone, which consists of four subunits: PIH1D1, RPAP3, RUVBL1, and RUVBL2. It is involved in the assembly of large protein or protein-RNA complexes such as RNA polymerase, small nucleolar ribonucleoproteins (snoRNPs), phosphatidylinositol 3 kinase-related kinases (PIKKs), and their complexes. While RPAP3 has a HSP90 binding domain and the RUVBLs comprise ATPase activities important for R2TP functions, PIH1D1 contains a PIH-N domain that specifically recognizes phosphorylated substrates of the R2TP complex. In this review we provide an overview of the current knowledge of the R2TP complex with the focus on the recently identified structural and mechanistic features of the R2TP complex functions. We also discuss the way R2TP regulates cellular response to stress caused by low levels of nutrients or by DNA damage and its possible exploitation as a target for anti-cancer therapy.
    Frontiers in Genetics 02/2015; 6:69. DOI:10.3389/fgene.2015.00069
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    • "Also, Izumi and colleagues recently validated the binding of URI to RUVBL1 and RUVBL2 by co-immunoprecipiation assays using Hela cell extracts [20] and demonstrated that RUVBL1, RUVBL2 and URI are part of a putative chaperone-regulatory complex that regulates and stabilizes the phosphatidylinositol 3-kinase-related protein kinases (PIKK) [21]. Interestingly, Pontin/RUVBL1 and Reptin/RUVBL2 have been shown to repress the transcription of several genes regulated by c-Myc, E2F1 and NF-kB [22]. Because of their biological relevance we decided to investigate if, as for other members of the R2TP/prefoldin-like complex, URI depletion or overexpression affected the cellular levels of the two RUVB-like proteins. "
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    ABSTRACT: Unconventional prefoldin RPB5 Interactor (URI) was identified as a transcriptional repressor that binds RNA polymerase II (pol II) through interaction with the RPB5/POLR2E subunit. Despite the fact that many other proteins involved in transcription regulation have been shown to interact with URI, its nuclear function still remains elusive. Previous mass spectrometry analyses reported that URI is part of a novel protein complex called R2TP/prefoldin-like complex responsible for the cytoplasmic assembly of RNA polymerase II. We performed a mass spectrometry (MS)-based proteomic analysis to identify nuclear proteins interacting with URI in prostate cells. We identified all the components of the R2TP/prefoldin-like complex as nuclear URI interactors and we showed that URI binds and regulates RPB5 protein stability and transcription. Moreover, we validated the interaction of URI to the P53 and DNA damage-Regulated Gene 1 (PDRG1) and show that PDRG1 protein is also stabilized by URI binding. We present data demonstrating that URI nuclear/cytoplasmic shuttling is affected by compounds that stall pol II on the DNA (α-amanitin and actinomycin-D) and by leptomycin B, an inhibitor of the CRM1 exportin that mediates the nuclear export of pol II subunits. These data suggest that URI, and probably the entire R2TP/prefoldin-like complex is exported from the nucleus through CRM1. Finally we identified putative URI sites of phosphorylation and acetylation and confirmed URI sites of post-transcriptional modification identified in previous large-scale analyses the importance of which is largely unknown. However URI post-transcriptional modification was shown to be essential for URI function and therefore characterization of novel sites of URI modification will be important to the understanding of URI function.
    PLoS ONE 05/2013; 8(5):e63879. DOI:10.1371/journal.pone.0063879 · 3.23 Impact Factor
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    • "RuvBL1 and RuvBL2 are essential components of several unrelated multi-protein complexes (3), including INO80 and SWR1 chromatin remodelling complexes (4), the TIP60 histone acetyltransferese complex (5), the R2TP complex involved in biogenesis of small nucleolar ribonucleoproteins (snoRNPs) (6,7) and complexes that regulate the activity of phosphatidylinositol 3-kinase (PI3K)-like kinases (8). RuvBL1 and RuvBL2 have been implicated in multiple and essential functions in the cell (1,3), including transcription (9), DNA repair (8), nonsense-mediated mRNA decay (NMD) (8) and telomerase assembly (10). In addition, several studies have described a link between deregulation of RuvBL1 and RuvBL2 and some types of cancer (11–13). "
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    ABSTRACT: RuvBL1 and RuvBL2, also known as Pontin and Reptin, are AAA+ proteins essential in small nucleolar ribonucloprotein biogenesis, chromatin remodelling, nonsense-mediated messenger RNA decay and telomerase assembly, among other functions. They are homologous to prokaryotic RuvB, forming single- and double-hexameric rings; however, a DNA binding domain II (DII) is inserted within the AAA+ core. Despite their biological significance, questions remain regarding their structure. Here, we report cryo-electron microscopy structures of human double-ring RuvBL1-RuvBL2 complexes at ∼15 Å resolution. Significantly, we resolve two coexisting conformations, compact and stretched, by image classification techniques. Movements in DII domains drive these conformational transitions, extending the complex and regulating the exposure of DNA binding regions. DII domains connect with the AAA+ core and bind nucleic acids, suggesting that these conformational changes could impact the regulation of RuvBL1-RuvBL2 containing complexes. These findings resolve some of the controversies in the structure of RuvBL1-RuvBL2 by revealing a mechanism that extends the complex by adjustments in DII.
    Nucleic Acids Research 08/2012; 40(21-1-14). DOI:10.1093/nar/gks871 · 9.11 Impact Factor
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