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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    • "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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    • "However, the mechanisms to control a p53-dependent apoptosis have yet to be fully elucidated. Pontin is a member of AAA+ ATPase family and functions as a transcriptional coactivator for various transcription factors such as T cell factor (TCF) and androgen receptor [10] [11] [12] [13] [14] [15]. In addition, Pontin has been shown to block p53-mediated apoptosis by repressing p53 expression and its target genes [16]. "
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    ABSTRACT: Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Based on high expression in lymphoid tissues, we examined whether Pontin has a T cell-specific function. We generated Pontin(f/f); Lck-Cre mice, in which Pontin can be conditionally deleted in T cells and then explored T cell-specific function of Pontin in vivo. Here, we show that specific abrogation of Pontin expression in T cells almost completely blocked development of αβ T cells at the β-selection checkpoint by inducing cell apoptosis indicating that Pontin is essential for early T cell development. Pontin-deficient thymocytes show a comparable expression level of T cell receptor (TCR) β chain, but have enhanced activation of p53 and Notch signaling compared to wild-type thymocytes. Intriguingly, the developmental block of αβ T cells can be partially rescued by loss of p53. Together, our data demonstrate a novel role of Pontin as a crucial regulator in pre-TCR signaling during T cell development.
    Biochemical and Biophysical Research Communications 03/2014; 447(1). DOI:10.1016/j.bbrc.2014.03.092 · 2.30 Impact Factor
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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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