PNUTS/PP1 Regulates RNAPII-Mediated Gene Expression and Is Necessary for Developmental Growth

Ciurciu, Anita; Duncalf, Louise; Jonchère, Vincent; Lansdale, Nick; Vasieva, Olga; Glenday, Peter; Rudenko, Andrii; Vissi, Emese; Cobbe, Neville; Alphey, Luke; Bennett, Daimark

doi:10.1371/journal.pgen.1003885

Cited by 50 publications

(84 citation statements)

References 76 publications

(87 reference statements)

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“…shown to associate with RNA polymerase II (RNAPII) at active sites of transcription and enhance the dephosphorylation of the RNAPII C-terminal domain (CTD) residue Ser5 (20,21). Remarkably, despite its role in these processes, the molecular function of PNUTS is still largely uncharacterized.…”

mentioning

confidence: 99%

Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code

Choy

Hieke

Kumar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

195

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The serine/threonine protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. However, how these proteins direct PP1 specificity and the ability to predict how these PP1 interacting proteins bind PP1 from sequence alone is still missing. PP1 nuclear targeting subunit (PNUTS) is a PP1 targeting protein that, with PP1, plays a central role in the nucleus, where it regulates chromatin decondensation, RNA processing, and the phosphorylation state of fundamental cell cycle proteins, including the retinoblastoma protein (Rb), p53, and MDM2. The molecular function of PNUTS in these processes is completely unknown. Here, we show that PNUTS, which is intrinsically disordered in its free form, interacts strongly with PP1 in a highly extended manner. Unexpectedly, PNUTS blocks one of PP1's substrate binding grooves while leaving the active site accessible. This interaction site, which we have named the arginine site, allowed us to define unique PP1 binding motifs, which advances our ability to predict how more than a quarter of the known PP1 regulators bind PP1. Additionally, the structure shows how PNUTS inhibits the PP1-mediated dephosphorylation of critical substrates, especially Rb, by blocking their binding sites on PP1, insights that are providing strategies for selectively enhancing Rb activity.nuclear phosphatases | enzyme regulation | enzyme specificity | X-ray crystal structure | nuclear magnetic resonance P rotein phosphatase 1 (PP1; ∼38.5 kDa), a single-domain protein, is the most widely expressed and abundant serine/threonine phosphatase (1). By dephosphorylating a variety of protein substrates, PP1 regulates diverse biological processes, including protein synthesis, muscle contraction, carbohydrate metabolism, neuronal signaling and, of specific interest for this work, cell-cycle progression. Although the intrinsic substrate specificity of PP1 is very low, by interacting with regulatory proteins (∼200 biochemically confirmed PP1 interactors), PP1 achieves high specificity (2-5). The majority of PP1 regulators and some substrates bind PP1 via a primary PP1-binding motif, the RVxF motif, which binds to a hydrophobic groove on PP1 ∼20 Å distal from its catalytic center (6). Outside of the RVxF motif, PP1 regulatory proteins mostly lack any apparent sequence similarity. Thus, additional interaction sites, such as the SILK (7), the MyPhoNE (8), and the recently identified ΦΦ motif (9) can only be identified by structural analysis, a major challenge for a comprehensive understanding of PP1 regulation. Only when the primary sequences of PP1 regulators are correlated with specific PP1 binding modes and activities will the PP1 interactome, and the biological processes it regulates, become a viable drug target for the multitude of PP1-associated diseases, such as multiple cancers.One of the key PP1 regulatory targeting proteins in the nucleus, in addition to nuclear inhibitor of PP1 (NIPP1) and Repoman, is the...

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mentioning

confidence: 99%

Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code

Choy

Hieke

Kumar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

195

View full text Add to dashboard Cite

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“…2A, Table 1) in nuclear extracts and is also able to dephosphorylate the C-terminal domain of this polymerase, at least in vitro [34,47]. Recently it was shown that PNUTS:PP1 complex enhances the dephosphorylation of RNAPII C-terminal domain (CTD) residue Ser5 [48,49].…”

Section: Gene Transcription and Rna Processingmentioning

confidence: 99%

Protein phosphatase 1 is a key player in nuclear events

Rebelo

Santos

Martins

et al. 2015

Cellular Signalling

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“…BCAR4 is required for the transcriptional activation of phospho-GLI2-dependent target genes in breast cancer cells. In response to CCL21, BCAR4 binds to Smad Nuclear Interacting Protein 1 (SNIP1) (109) and serine/threonine phosphatase regulatory subunit 10 (PSP1R10) also known as PNUTS (110). Interaction of phospho-GLI2 with SNIP1 releases SNIP1-mediated inhibition of p300-dependent histone acetylation, which results in binding of PNUTS to H3K18ac, thereby releasing inhibition of pol II via activation of phosphatase PP1 ( Figure 1F) (111).…”

Section: Lncrna Bcar4 (Breast Cancer Anti-estrogen Resistance)mentioning

confidence: 99%

Long Non-coding RNAs and their Role in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

168

124

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Abstract.Metastasis is the major cause of death in patients with cancer. It is mediated by a multi-step process referred to as the metastatic cascade (1, 2). Initial steps include local invasion and migration, angiogenesis, epithelialmesenchymal transition (EMT) and intravasation. Tumor cells enter the circulation as single cells or circulating tumor cell clusters, are coated by platelets to escape an immune response and subsequently arrest in capillaries in distant organs as a prerequisite for extravasation. Colonization starts by homing of tumor cells in supporting niches of the organ parenchyma, followed by a latency phase which can last from several months to decades. A prerequiste for overt outgrowth of micrometastases is their adaptation to the local microenvironment and acquisition of colonisation-promoting traits (3-6). The pattern of colonized distant organs depends on the tumor type and can range from predominant spread to one organ and colonization of different types of organs sequentially or simultaneously (7). Several genes and their products have been identified to mediate crucial steps of the metastatic process such as metastasis initiation and progression, as well as organ-specific functions of metastasis (virulence) (8, 9). These gene products include proteases, chemokines, cytokines and their receptors, angiogenic factors, intracellular and transmembrane kinases, adhesion molecules, components of the extracellular matrix (ECM), GPI-linked receptors and carbohydrate metabolism-related enzymes (8, 9). More recently, an important impact of RNA-related molecules for metastasis has emerged. MicroRNAs (miRs) and other types of RNA modulate metastasis via regulatory networks (10,11). In this review we focus on the role of long non-coding RNAs (lncRNA) as promoters or inhibitors of metastasis in different tumor entities since there is an urgent need to define new targets for therapeutic intervention. With the exception of denosumab for treatment of bone metastases, all other agents evaluated in clinical studies for treatment of metastatic disease gave rise to mixed or disappointing results (6).

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PNUTS/PP1 Regulates RNAPII-Mediated Gene Expression and Is Necessary for Developmental Growth

Cited by 50 publications

References 76 publications

Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code

Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code

Protein phosphatase 1 is a key player in nuclear events

Long Non-coding RNAs and their Role in Metastasis

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