Affinage

PPP1R10

Serine/threonine-protein phosphatase 1 regulatory subunit 10 · UniProt Q96QC0

Length
940 aa
Mass
99.1 kDa
Annotated
2026-06-10
72 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R10 (PNUTS/p99) is the principal nuclear targeting subunit of protein phosphatase 1 (PP1), forming a stable holoenzyme that directs and constrains PP1 catalytic activity on chromatin to control transcription, cell cycle progression, and genome stability (PMID:9461602, PMID:9450550). PNUTS binds PP1 through a central ~50-residue domain in a highly extended, intrinsically disordered conformation, using an RVXF-like motif in which a critical tryptophan (W401) replaces the canonical phenylalanine; this contact blocks one of PP1's substrate-binding grooves to inhibit dephosphorylation of substrates such as Rb while leaving the active site available, and the W401A mutation abolishes both binding and the holoenzyme's activities (PMID:9450550, PMID:12574161, PMID:24591642, PMID:15907195). PKA phosphorylation of the PP1-binding domain reduces PNUTS–PP1 association, providing a regulatory switch (PMID:12574161). The PNUTS–PP1 complex governs RNA Pol II dynamics genome-wide: it dephosphorylates the elongation factor Spt5 to decelerate Pol II and is required for transcription pause release as well as for termination, where Pol II deceleration downstream of poly(A) sites enables a 'sitting duck torpedo' mechanism (PMID:31677974, PMID:39603239). Through direct binding to WDR82 and proximity to the Restrictor complex (ZC3H4/WDR82/ARS2) and Symplekin, PNUTS–PP1 dephosphorylates the Pol II CTD (Ser5) to enforce termination of protein-coding, antisense, and extragenic noncoding transcripts (PMID:37329883, PMID:38092518, PMID:40244850). Beyond transcription, PNUTS–PP1 dephosphorylates and stabilizes MYC at target-gene promoters via a direct MYC MB0–PNUTS PAD interaction, controlling MYC chromatin binding and SCF^FBXW7-mediated turnover (PMID:30158517, PMID:35244724); promotes chromosome decondensation in telophase (PMID:15907195); restrains ATR signaling and replication stress in a manner dependent on the phospho-CTD reader CDC73 (PMID:33264625, PMID:30541148); and controls CENP-A deposition through a PP1→DAXX pathway, maintaining kinetochore integrity and chromosomal stability (PMID:40270285). PNUTS additionally acts as a PP1-independent scaffold, sequestering PTEN in the nucleus via its C2 domain (PMID:23117887) and bridging PP1 to partners including GABA(C) receptors and the transcriptional regulator LCP1 (PMID:19293638, PMID:18325784). Endothelial PNUTS is required for vascular integrity in vivo, acting through the PNUTS–PP1 axis to repress SEMA3B (PMID:38714838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1997 High

    Establishing that PPP1R10 is a bona fide PP1 regulatory subunit answered whether this nuclear protein controls phosphatase output, showing it potently inhibits PP1 catalytic activity.

    Evidence Biochemical purification of p99 from HeLa nuclei with in vitro phosphatase assays, identifying an atypical Trp in the PP1-binding motif

    PMID:9450550 PMID:9461602

    Open questions at the time
    • Physiological substrates of the holoenzyme not yet defined
    • Functional consequence of the atypical Trp motif unresolved
  2. 2003 High

    Mapping the PP1-binding determinant defined how PNUTS docks and is regulated, identifying the essential W residue, PKA-dependent control, and a separable nucleic-acid-binding C-terminus.

    Evidence Truncation/mutagenesis with GST pulldown, in vitro phosphatase and PKA kinase assays, and RNA/ssDNA binding in 293T cells

    PMID:12574161

    Open questions at the time
    • In vivo relevance of RNA binding not established
    • Which substrates are gated by PKA phosphorylation unknown
  3. 2014 High

    Atomic-resolution structure explained the inhibitory mechanism, showing PNUTS binds PP1 in an extended manner and occludes the arginine substrate groove rather than the active site.

    Evidence NMR and X-ray crystallography of the PNUTS–PP1 complex with biochemical and mutagenesis validation against Rb dephosphorylation

    PMID:24591642

    Open questions at the time
    • Structure of full-length, intrinsically disordered PNUTS not determined
    • How substrate selectivity is achieved in cells not resolved
  4. 2002 Medium

    Linking PNUTS to Rb dephosphorylation answered which cell-cycle substrate the holoenzyme gates, showing PNUTS inhibits PP1 toward pRb and dissociates under hypoxia.

    Evidence In vitro pRb-directed phosphatase assay with GST-PNUTS and hypoxia treatment of cells

    PMID:12270115

    Open questions at the time
    • Mechanism coupling hypoxia to PNUTS–PP1 dissociation unknown
    • Cellular hypoxia correlate not mechanistically tied to phosphatase change
  5. 2005 High

    Connecting PNUTS to mitotic exit showed the holoenzyme drives chromatin decondensation, establishing a structural role for PP1 targeting at telophase.

    Evidence Subcellular fractionation, in vitro chromosome decondensation assays in defined buffer, and W401A mutagenesis

    PMID:15907195

    Open questions at the time
    • Direct chromatin substrate dephosphorylated during decondensation not identified
    • Recruitment mechanism to reforming nuclei unclear
  6. 2008 Medium

    Genetic epistasis defined the consequence of losing PNUTS in cancer cells, showing PNUTS loss unleashes PP1 on Rb to trigger E2F1 release and caspase-8 apoptosis selectively in Rb-expressing cells.

    Evidence siRNA knockdown with Rb-null vs Rb-expressing cell panel, Rb-phosphatase and apoptosis assays

    PMID:18360108

    Open questions at the time
    • Single lab
    • Why normal cells are spared not mechanistically resolved
  7. 2008 Medium

    Discovery of a PNUTS–PP1–GABA(C) receptor complex showed PNUTS can act as a membrane-targeting scaffold outside the nucleus.

    Evidence Co-IP, subcellular fractionation, and localization shift upon receptor co-expression in retinal bipolar cells

    PMID:18325784

    Open questions at the time
    • Functional output of receptor-associated PP1 not defined
    • Single lab; physiological context limited
  8. 2009 Medium

    Identifying the PNUTS–LCP1 interaction showed PNUTS has a PP1-independent transcriptional-repression function distinct from its phosphatase-targeting role.

    Evidence Yeast two-hybrid, Co-IP domain mapping, nuclear speckle co-localization, and GAL4 reporter assays

    PMID:19293638

    Open questions at the time
    • Endogenous target genes of LCP1 repression unknown
    • Single lab
  9. 2010 High

    Implicating PNUTS in the DNA damage response showed it restrains G2 checkpoint activation and supports repair, recruiting transiently to damage sites.

    Evidence siRNA knockdown, live-cell imaging of PNUTS-EGFP recruitment, cell-cycle flow cytometry, repair foci, and clonogenic survival after IR

    PMID:20890310

    Open questions at the time
    • Substrate dephosphorylated at damage sites not identified
    • Whether checkpoint role is PP1-dependent not directly tested here
  10. 2012 Medium

    Identifying PTEN sequestration showed PNUTS scaffolds a tumor suppressor in the nucleus, defining a PP1-independent function via the PTEN C2 domain.

    Evidence Co-IP, GST pulldown domain mapping, siRNA knockdown with PTEN-dependent viability/apoptosis readouts

    PMID:23117887

    Open questions at the time
    • Regulation of PTEN nuclear/cytoplasmic shuttling by PNUTS unclear
    • Single lab
  11. 2015 Medium

    Linking PNUTS to HIV-1 transcription showed it negatively regulates P-TEFb assembly, embedding it in a viral miR-34a feedback loop.

    Evidence Overexpression/knockdown, HIV-1 LTR luciferase reporter, Co-IP of cyclin T1/CDK9, and replication assays

    PMID:26188041

    Open questions at the time
    • Whether PP1 activity is required for P-TEFb inhibition not resolved
    • Single lab
  12. 2018 High

    Defining the MYC connection showed PNUTS–PP1 dephosphorylates and stabilizes MYC at promoters, controlling MYC chromatin binding and FBXW7-mediated turnover.

    Evidence BioID-MS, Co-IP, ChIP, RNAi, pharmacological PP1 inhibition, and phospho-site mass spectrometry across multiple cell types

    PMID:30158517

    Open questions at the time
    • Direct PNUTS-PP1 MYC phospho-sites not all mapped to function in this study
    • Interface of MYC contact not yet structurally defined here
  13. 2018 Medium

    Linking PNUTS to mitotic fidelity showed it associates with Aurora kinases/kinetochore components and is required for CPC regulation and spindle checkpoint signaling.

    Evidence siRNA knockdown, Co-IP/MS, kinetochore immunofluorescence, kinase assays, and live-cell imaging

    PMID:30190438

    Open questions at the time
    • Whether PNUTS-PP1 phosphatase activity drives Aurora regulation not separated
    • Single lab
  14. 2019 High

    Genome-wide elongation profiling established that PNUTS-PP1 decelerates Pol II via Spt5 dephosphorylation, defining a 'sitting duck torpedo' termination model dependent on poly(A) recognition.

    Evidence TT-seq, ChIP-seq, W401A mutagenesis, and phospho-Spt5 analysis with in vivo elongation rate measurement

    PMID:31677974

    Open questions at the time
    • How poly(A) site recognition is coupled to PP1 recruitment unresolved
    • Full set of CTD/elongation substrates not enumerated
  15. 2019 Medium

    Connecting PNUTS-PP1 to replication stress showed that loss elevates ATR signaling via R-loops in a CDC73-dependent manner, independent of canonical damage markers.

    Evidence siRNA knockdown, pATR/γH2AX immunofluorescence, R-loop detection, Co-IP of ATR/RNAPII/CDC73, and cell-cycle analysis

    PMID:30541148

    Open questions at the time
    • Mechanism by which CDC73 promotes R-loops not defined
    • Single lab
  16. 2020 High

    Showing PNUTS-PP1 suppresses replication stress via CTD dephosphorylation established that it limits RNAPII chromatin residence and promotes proteasomal RNAPII turnover with WDR82.

    Evidence siRNA knockdown, EdU incorporation, FRAP of RNAPII, DNA fiber assays, proteasome inhibition, and CDC73 epistasis

    PMID:33264625

    Open questions at the time
    • Direct trigger for proteasomal RNAPII degradation unclear
    • How transcription-replication conflicts are resolved mechanistically open
  17. 2022 High

    Structural definition of the MYC–PNUTS interface answered how PNUTS engages MYC, showing MYC MB0 binds the PNUTS PAD and that interface mutations elevate MYC phosphorylation.

    Evidence NMR solution structure of PAD, in vitro binding, mutagenesis, and cellular Co-IP

    PMID:35244724

    Open questions at the time
    • How PP1 catalysis is positioned on MYC by this interface not shown
    • In vivo tumor relevance of interface mutations untested here
  18. 2023 High

    Connecting PNUTS to the Restrictor pathway showed it enables termination of all major Pol II transcript classes, with U1 snRNA shielding coding transcripts.

    Evidence siRNA knockdown, ChIRP/ChIP, and nascent RNA sequencing with epistasis

    PMID:37329883

    Open questions at the time
    • Molecular basis of PNUTS–Restrictor proximity not structurally defined here
    • How U1 antagonizes PNUTS function unresolved
  19. 2023 Medium

    Defining PNUTS–Symplekin cooperation showed PNUTS dampens processive extragenic transcription synergistically with, but independently from, Restrictor.

    Evidence siRNA knockdown and nascent RNA sequencing with genetic epistasis

    PMID:38092518

    Open questions at the time
    • Mechanistic basis of Symplekin synergy unclear
    • Single lab
  20. 2024 High

    Establishing PNUTS-PP1 in pause release showed it is required for nearly all Pol II-dependent transcription, dependent on PP1 catalytic activity.

    Evidence CRISPR/genetic depletion, ChIP-seq, nascent RNA sequencing, and W401A mutant analysis

    PMID:39603239

    Open questions at the time
    • Specific pause-release substrate phospho-sites not fully mapped
    • How pause-release and termination roles are temporally coordinated open
  21. 2024 High

    An endothelial conditional knockout established an in vivo physiological role, showing PNUTS-PP1 maintains vascular barrier function by repressing SEMA3B.

    Evidence Cdh5-CreERT2;PNUTSfl/fl mice, siRNA knockdown, transcriptomics, barrier/senescence assays, and SEMA3B rescue

    PMID:38714838

    Open questions at the time
    • How PNUTS-PP1 controls SEMA3B transcription mechanistically unclear
    • Tissue specificity of the phenotype not fully explained
  22. 2025 High

    Substrate-trap dissection of the PPWZ complex showed PNUTS binds WDR82 directly and that PP1 catalytic activity dephosphorylating CTD Ser5 is required for Restrictor-mediated termination.

    Evidence Co-IP, AlphaFold modeling, dominant-negative PP1H66K substrate trap, NET-seq, ChIP-seq, and CTD phospho-state analysis

    PMID:40244850

    Open questions at the time
    • Experimental structure of the PPWZ quaternary complex lacking
    • How CTD Ser5 dephosphorylation increases pausing mechanistically open
  23. 2025 Medium

    Defining a PNUTS→PP1→DAXX axis showed PNUTS controls CENP-A deposition and chromosomal stability, with DAXX loss suppressing CENP-A mislocalization.

    Evidence Genome-wide siRNA screen, knockdown, CENP-A/CENP-C immunofluorescence, micronuclei scoring, and DAXX epistasis

    PMID:40270285

    Open questions at the time
    • Direct PP1 substrate in the DAXX pathway not identified
    • Single lab
  24. 2025 Medium

    Drosophila studies extended PNUTS function to germline biology, showing zinc-dependent Tox4 binding to the PNUTS TND and roles in transposon silencing via SFiNX/Senataxin.

    Evidence Biochemical/structural binding assays and in vivo Drosophila genetics, transcriptomics, and Pol II ChIP

    PMID:40347473 PMID:41167190

    Open questions at the time
    • Conservation of these roles in mammals untested
    • Drosophila ortholog; direct PP1 substrates in transposon silencing unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple PNUTS-PP1 chromatin functions (pause release, termination, CTD/Spt5 dephosphorylation, CENP-A deposition, MYC stabilization, DNA damage response) are spatially and temporally coordinated by a single targeting subunit remains unresolved.
  • No unifying model for substrate selection in vivo
  • Structure of full-length PNUTS holoenzyme on chromatin lacking
  • Direct dephosphorylation substrate maps incomplete for most pathways

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 1 GO:0003723 RNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005694 chromosome 2 GO:0005730 nucleolus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-73894 DNA Repair 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CDC73LCP1MYCPPP1CAPTENTOX4WDR82ZC3H4
Complex memberships
PNUTS-PP1 holoenzymePPWZ complex (PP1-PNUTS-WDR82-ZC3H4)Restrictor complex (ZC3H4/WDR82/ARS2)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PNUTS (PPP1R10) was identified as a PP1-interacting protein that forms a stable complex with PP1 in mammalian cell lysates, potently modulates PP1 catalytic activity toward exogenous substrates in vitro, and exhibits discrete nuclear compartmentalization with co-localization with chromatin during mitosis. Yeast two-hybrid, co-immunoprecipitation from mammalian cell lysates, in vitro phosphatase activity assay, immunofluorescence The Journal of biological chemistry High 9461602
1997 p99 (PPP1R10) was purified as a PP1 regulatory subunit from HeLa cell nuclei; recombinant p99 suppresses PP1 phosphorylase phosphatase activity by >90%; the PP1-binding motif contains an unusual tryptophan in place of the canonical phenylalanine; p99 shows punctate nucleoplasmic staining with nucleolar accumulations. Biochemical purification from HeLa nuclei, in vitro phosphatase activity assay, immunofluorescence, cDNA cloning FEBS letters High 9450550
2003 A 50-amino acid central domain of PNUTS mediates high-affinity PP1 binding and inhibition of PP1 activity; the critical tryptophan residue within the RVXF-like motif is essential (W→A mutation abolishes PP1 binding and inhibition); protein kinase A phosphorylates this PP1-binding domain and substantially reduces PNUTS–PP1 interaction in vitro and in intact cells upon PKA stimulation; a C-terminal region containing RGG motifs and His/Gly-rich repeats binds mRNA and ssDNA with selectivity for poly(A) and poly(G); a PNUTS–PP1 complex can be isolated via RNA-conjugated beads. GST pulldown, FLAG-tagged protein expression in 293T cells, in vitro phosphatase assay, in vitro kinase assay (PKA), in vitro RNA binding, site-directed mutagenesis, truncation analysis The Journal of biological chemistry High 12574161
2014 PNUTS is intrinsically disordered in its free form and binds PP1 in a highly extended manner; PNUTS blocks one of PP1's substrate-binding grooves (the 'arginine site') while leaving the active site accessible, thereby inhibiting PP1-mediated dephosphorylation of Rb by blocking Rb's binding site on PP1; unique PP1-binding motifs defined by the PNUTS–PP1 structure allow prediction of how >25% of known PP1 regulators bind PP1. NMR structure determination, X-ray crystallography, biochemical binding assays, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 24591642
2005 PNUTS co-fractionates with micrococcal nuclease-soluble chromatin in interphase and is targeted to reforming nuclei in telophase concomitant with chromatin decondensation; recombinant PNUTS(309-691) accelerates decondensation of prometaphase chromosomes in vitro in a manner requiring the RVXF PP1-binding motif (W401A mutation abolishes activity); PNUTS promotes decondensation via the PNUTS:PP1 holoenzyme in a defined buffer system with exogenous PP1. Subcellular fractionation, in vitro chromosome decondensation assay (cytosolic extract and defined buffer system), immunofluorescence, site-directed mutagenesis (W401A) The Biochemical journal High 15907195
2002 PNUTS inhibits PP1c activity toward pRb; GST-PNUTS fusion protein inhibits pRb-directed PP1c activity using PP1c from cell lysates, GST-PP1c, or purified PP1c; PNUTS dissociates from PP1c under mildly hypoxic conditions coincident with increased PP1c activity toward pRb. In vitro pRb-directed phosphatase assay, GST pulldown, hypoxia treatment of cells Biochemical and biophysical research communications Medium 12270115
2008 Reduced expression of PNUTS in cancer cells increases PP1 activity toward Rb, leading to Rb dephosphorylation, dissociation of E2F1 from Rb, and caspase-8-dependent apoptosis; this effect requires Rb (no effect in Rb-null cells) and is p53-independent; normal cells are not affected by PNUTS knockdown. siRNA knockdown, cell viability assay, apoptosis assay, Rb-phosphatase activity assay, cell line panel (Rb-null vs. Rb-expressing) Cancer biology & therapy Medium 18360108
2010 PNUTS depletion by siRNA activates a G2 checkpoint in unperturbed cells and prolongs G2 arrest and Chk1 activation after ionizing-radiation-induced DNA damage; overexpression of PNUTS-EGFP, which rapidly and transiently localizes to DNA damage sites, inhibits G2 arrest; PNUTS depletion causes prolonged γH2AX, 53BP1, RPA, and Rad51 foci and decreased clonogenic survival after irradiation. siRNA knockdown, live-cell imaging (PNUTS-EGFP recruitment to damage sites), flow cytometry (cell cycle), immunofluorescence (γH2AX, 53BP1, RPA, Rad51), clonogenic survival assay EMBO reports High 20890310
2012 PNUTS directly interacts with the C2 (lipid-binding) domain of PTEN and sequesters PTEN in the nucleus; depletion of PNUTS leads to increased apoptosis and reduced proliferation in a PTEN-dependent manner. Co-immunoprecipitation, GST pulldown (domain mapping), siRNA knockdown, cell viability and apoptosis assays Cancer research Medium 23117887
2018 Endogenous MYC and PNUTS interact across multiple cell types and co-occupy MYC target gene promoters; PP1/PNUTS dephosphorylates MYC at multiple serine/threonine residues; inhibiting PP1 causes MYC hyperphosphorylation, proteasomal degradation via SCFFBXW7, and loss of MYC chromatin binding while retaining MAX interaction; rescue requires specifically PP1, not other phosphatases. BioID mass spectrometry, co-immunoprecipitation, ChIP, RNAi knockdown, pharmacological PP1 inhibition, phospho-site mass spectrometry Nature communications High 30158517
2019 PNUTS-PP1 is a negative regulator of RNA Pol II elongation rate; the PNUTS W401A mutation (disrupting PP1 binding) causes genome-wide acceleration of transcription associated with hyper-phosphorylation of the Spt5 elongation factor; Pol II decelerates immediately downstream of poly(A) sites, correlating with Spt5 dephosphorylation requiring poly(A) site recognition and the PNUTS-PP1 complex; PNUTS-PP1-dependent Pol II deceleration is required for transcription termination ('sitting duck torpedo' mechanism). TT-seq (transient transcriptome sequencing), ChIP-seq, site-directed mutagenesis (W401A), in vivo elongation rate measurement, phospho-Spt5 analysis Molecular cell High 31677974
2018 PNUTS expression is elevated in mitosis; PNUTS depletion partially blocks mitotic entry and causes chromosome mis-segregation; Aurora A/B kinase complexes and kinetochore components are PNUTS-associated proteins; PNUTS depletion suppresses Aurora A/B activation and disrupts chromosomal passenger complex (CPC) spatiotemporal regulation; PNUTS dynamically localizes to kinetochores and is required for spindle assembly checkpoint activation. siRNA knockdown, co-immunoprecipitation/MS, immunofluorescence (kinetochore localization), kinase activity assay, live-cell imaging Molecular cancer research : MCR Medium 30190438
2020 PNUTS-PP1 promotes RNAPII CTD dephosphorylation and suppresses replication stress; PNUTS depletion causes lower EdU uptake, S-phase accumulation, and slower replication fork rates; RNAPII has a longer chromatin residence time after PNUTS or WDR82 depletion; PNUTS and WDR82 promote proteasome-dependent degradation of RNAPII on chromatin; reduced replication after PNUTS/WDR82 depletion depends on transcription and the phospho-CTD binding protein CDC73. siRNA knockdown, EdU incorporation, FRAP (RNAPII residence time), replication fork rate assay (DNA fiber), proteasome inhibition, epistasis with CDC73 Cell reports High 33264625
2019 ATR signaling is increased after depletion of PNUTS-PP1 (the RNAPII-CTD phosphatase); elevated ATR signaling is independent of DNA damage markers or RPA chromatin loading but correlates with R-loop formation; CDC73, which interacts with phospho-CTD RNAPII, is required for high ATR signaling, R-loop formation, and G2 checkpoint activation after PNUTS depletion; ATR, RNAPII, and CDC73 co-immunoprecipitate. siRNA knockdown, immunofluorescence (γH2AX, pATR), R-loop detection, co-immunoprecipitation, cell cycle analysis Nucleic acids research Medium 30541148
2022 MYC directly interacts with PNUTS through MYC Homology Box 0 (MB0) and the PNUTS amino-terminal domain (PAD, residues 1–148); NMR solution structure of PAD was determined and the MYC-binding patch characterized; point mutations at the MYC-PNUTS interface weaken interaction in vitro and in vivo and lead to elevated MYC phosphorylation. NMR spectroscopy (solution structure), in vitro binding assays, site-directed mutagenesis, cellular co-immunoprecipitation Nucleic acids research High 35244724
2009 PNUTS interacts with LCP1 (an HMG-box protein) through PNUTS's N-terminal region (distinct from the PP1-binding domain) and LCP1's C-terminus; a subpopulation of LCP1 co-localizes with PNUTS in nuclear speckles; PNUTS interaction with LCP1 markedly suppresses LCP1 transcriptional activation activity in a PP1-independent manner. Yeast two-hybrid, co-immunoprecipitation of deletion constructs, immunofluorescence, GAL4-based transcription reporter assay Experimental & molecular medicine Medium 19293638
2008 PNUTS forms a trimeric complex with GABA(C) receptors and PP1 in retinal bipolar cells; PNUTS and PP1 are detected in membrane fractions and co-precipitate with GABA(C) receptor antibodies; GABA(C) receptor co-expression causes PNUTS to shuttle from nucleus to membrane; simultaneous binding of PP1 and GABA(C) receptors to distinct domains of PNUTS was demonstrated. Co-immunoprecipitation, subcellular fractionation, immunofluorescence (localization shift), domain binding analysis Molecular and cellular neurosciences Medium 18325784
2015 PNUTS negatively regulates HIV-1 transcription by inhibiting assembly of the core P-TEFb components cyclin T1 and CDK9; overexpression of PNUTS potently and dose-dependently inhibits HIV-1 replication; miR-34a (upregulated by HIV-1) promotes replication by targeting PNUTS, creating a positive feedback loop. Overexpression/knockdown, luciferase reporter (HIV-1 LTR), co-immunoprecipitation (P-TEFb assembly), viral replication assay The Biochemical journal Medium 26188041
2023 PNUTS is required for efficient termination of all major RNA Pol II transcript classes, including short ncRNAs and longer protein-coding transcripts; PNUTS is proximal to the Restrictor complex (ZC3H4-WDR82-ARS2) and enables Restrictor function; U1 snRNA shields coding transcripts from Restrictor and PNUTS at hundreds of genes. siRNA knockdown, ChIRP/ChIP, nascent RNA sequencing (TT-seq/GRO-seq), epistasis experiments Molecular cell High 37329883
2023 Efficient termination at Restrictor-controlled extragenic transcription units requires PNUTS (a negative regulator of SPT5 elongation factor) and Symplekin; PNUTS and Symplekin act synergistically with, but independently from, Restrictor to dampen processive extragenic transcription. siRNA knockdown, nascent RNA sequencing, epistasis experiments Genes & development Medium 38092518
2024 The PNUTS-PP1 complex plays an essential role in transcription pause release in addition to termination; pause release by PNUTS-PP1 is required for almost all RNA Pol II-dependent gene transcription; this function depends on PP1 phosphatase activity and controls phosphorylation of factors required for pause release and elongation. CRISPR/genetic depletion, ChIP-seq, nascent RNA sequencing, PP1-binding mutant (W401A) analysis Molecular cell High 39603239
2025 PP1/PNUTS co-purifies with the Restrictor complex (ZC3H4/WDR82); PNUTS binds directly to WDR82; AlphaFold predicts a quaternary PPWZ complex; a substrate-trap (inactive PP1H66K fused to PNUTS C-terminus) acts as dominant-negative inhibitor of antisense termination and CTD Ser5 dephosphorylation, demonstrating that phosphatase activity is required for restrictor-mediated termination; CTD Ser5 dephosphorylation by PPWZ promotes termination by increasing Pol II pausing. Co-immunoprecipitation, AlphaFold structural modeling, substrate-trap dominant-negative expression, NET-seq, ChIP-seq, CTD phospho-state analysis Cell reports High 40244850
2025 PNUTS depletion causes CENP-A mislocalization to non-centromeric regions and chromosomal instability (CIN) in a PP1-dependent manner; CENP-C also mislocalizes; kinetochore integrity defects and micronuclei are observed; depletion of the H3.3 chaperone DAXX suppresses CENP-A mislocalization and micronuclei in PNUTS-depleted cells, defining a PNUTS→PP1→DAXX pathway controlling CENP-A deposition. Genome-wide siRNA screen, siRNA knockdown, immunofluorescence (CENP-A, CENP-C), micronuclei scoring, genetic epistasis (DAXX depletion) Molecular and cellular biology Medium 40270285
2025 In Drosophila, Tox4 requires zinc for binding the PNUTS TFIIS N-terminal domain (TND); Tox4 binds TND on a surface distinct from established TND-interacting transcriptional regulators; selective disruption of PNUTS-Tox4 or PNUTS-PP1 interactions impairs normal gene expression and chromosomal dispersal during oogenesis; tox4 is dispensable for viability but essential for fertility with PNUTS-dependent and -independent roles. Biochemical binding assays, structural analysis, in vivo Drosophila genetics (fertility/oogenesis), transcriptomics, site-directed mutagenesis Cell reports Medium 40347473
2025 In Drosophila germline, PNUTS and Senataxin associate with the SFiNX complex via Sov to initiate transposon silencing independent of H1 and HP1a heterochromatin; PNUTS mechanistically affects RNA Pol II elongation speed or stalling to induce transcriptional repression of transposable elements prior to heterochromatinization. Co-immunoprecipitation/mass spectrometry, genetic epistasis (H1, HP1a mutants), RNA Pol II ChIP/elongation assays in Drosophila Molecular cell Medium 41167190
2016 The N-terminal domain of PNUTS (PAD) adopts a compact globular fold rich in α-helical content, resembling an extended transcription factor TFIIS (S-II) leucine/tryptophan conserved-motif fold, with a melting temperature of ~49.5°C; this domain mediates interactions with Tox4 and PTEN. Circular dichroism, NMR spectroscopy, thermal denaturation, bioinformatics The protein journal Medium 27591855
2024 PNUTS silencing in endothelial cells causes senescence, reduced angiogenesis, and loss of barrier function; PNUTS-PP1 axis regulates expression of semaphorin 3B (SEMA3B); silencing SEMA3B completely restores barrier function after PNUTS loss; endothelial-specific PNUTS knockout mice (Cdh5-CreERT2;PNUTSfl/fl) develop severe multiorgan failure and vascular leakage within two weeks. siRNA knockdown, conditional knockout mouse model (Cdh5-CreERT2;PNUTSfl/fl), transcriptomics, barrier function assays, senescence assays, epistasis (SEMA3B rescue) Communications biology High 38714838

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nature cell biology 272 28825698
1993 Evolution of an enzyme activity: crystallographic structure at 2-A resolution of cephalosporinase from the ampC gene of Enterobacter cloacae P99 and comparison with a class A penicillinase. Proceedings of the National Academy of Sciences of the United States of America 193 8248237
2019 Control of RNA Pol II Speed by PNUTS-PP1 and Spt5 Dephosphorylation Facilitates Termination by a "Sitting Duck Torpedo" Mechanism. Molecular cell 176 31677974
1994 Crystallographic structure of a phosphonate derivative of the Enterobacter cloacae P99 cephalosporinase: mechanistic interpretation of a beta-lactamase transition-state analog. Biochemistry 146 8204611
1998 Isolation and characterization of PNUTS, a putative protein phosphatase 1 nuclear targeting subunit. The Journal of biological chemistry 137 9461602
2010 Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrobial agents and chemotherapy 122 20921316
2014 Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code. Proceedings of the National Academy of Sciences of the United States of America 105 24591642
1987 Common mechanism of ampC beta-lactamase induction in enterobacteria: regulation of the cloned Enterobacter cloacae P99 beta-lactamase gene. Journal of bacteriology 92 3027046
1997 Purification and characterisation of p99, a nuclear modulator of protein phosphatase 1 activity. FEBS letters 78 9450550
2003 PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit. Characterization of its PP1- and RNA-binding domains and regulation by phosphorylation. The Journal of biological chemistry 69 12574161
1985 The beta-lactamase of Enterobacter cloacae P99. Chemical properties, N-terminal sequence and interaction with 6 beta-halogenopenicillanates. The Biochemical journal 65 2988516
2010 The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response. EMBO reports 64 20890310
2005 PNUTS enhances in vitro chromosome decondensation in a PP1-dependent manner. The Biochemical journal 57 15907195
2018 MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability. Nature communications 53 30158517
2020 WDR82/PNUTS-PP1 Prevents Transcription-Replication Conflicts by Promoting RNA Polymerase II Degradation on Chromatin. Cell reports 50 33264625
1984 The active site of the P99 beta-lactamase from Enterobacter cloacae. The Biochemical journal 48 6333871
2012 PNUTS functions as a proto-oncogene by sequestering PTEN. Cancer research 46 23117887
1992 Mechanism of inhibition of the class C beta-lactamase of Enterobacter cloacae P99 by phosphonate monoesters. Biochemistry 45 1610830
2008 Reduced expression of PNUTS leads to activation of Rb-phosphatase and caspase-mediated apoptosis. Cancer biology & therapy 41 18360108
2002 Mutational replacement of Leu-293 in the class C Enterobacter cloacae P99 beta-lactamase confers increased MIC of cefepime. Antimicrobial agents and chemotherapy 41 12019116
1972 Comparison of the substrate specificities of the -lactamases from Klebsiella aerogenes 1082E and Enterobacter cloacae P99. Applied microbiology 41 4553144
2023 A restrictor complex of ZC3H4, WDR82, and ARS2 integrates with PNUTS to control unproductive transcription. Molecular cell 39 37329883
2014 microRNA-383 impairs phosphorylation of H2AX by targeting PNUTS and inducing cell cycle arrest in testicular embryonal carcinoma cells. Cellular signalling 39 24462707
2002 PNUTS (phosphatase nuclear targeting subunit) inhibits retinoblastoma-directed PP1 activity. Biochemical and biophysical research communications 34 12270115
1996 Kinetics and mechanism of the hydrolysis of depsipeptides catalyzed by the beta-lactamase of Enterobacter cloacae P99. Biochemistry 34 8639511
2016 Bacteriocin-like substances of Lactobacillus curvatus P99: characterization and application in biodegradable films for control of Listeria monocytogenes in cheese. Food microbiology 30 28040164
2001 Amino acid sequence determinants of extended spectrum cephalosporin hydrolysis by the class C P99 beta-lactamase. The Journal of biological chemistry 29 11591698
1983 Crystallographic data for the beta-lactamase from Enterobacter cloacae P99. Journal of molecular biology 28 6606712
2015 The miRNA miR-34a enhances HIV-1 replication by targeting PNUTS/PPP1R10, which negatively regulates HIV-1 transcriptional complex formation. The Biochemical journal 23 26188041
2022 The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase. Nucleic acids research 22 35244724
2018 Phosphatase 1 Nuclear Targeting Subunit (PNUTS) Regulates Aurora Kinases and Mitotic Progression. Molecular cancer research : MCR 21 30190438
2001 Mechanism of inhibition of the class C beta-lactamase of Enterobacter cloacae P99 by cyclic acyl phosph(on)ates: rescue by return. Journal of the American Chemical Society 21 11673973
1996 Modifying the specificity and activity of the Enterobacter cloacae P99 beta-lactamase by mutagenesis within an M13 phage vector. Biochemistry 21 8652552
2023 Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription. Genes & development 19 38092518
2009 Langerhans cell protein 1 (LCP1) binds to PNUTS in the nucleus: implications for this complex in transcriptional regulation. Experimental & molecular medicine 17 19293638
2009 A crtA-related gene from Flavobacterium P99-3 encodes a novel carotenoid 2-hydroxylase involved in myxol biosynthesis. FEBS letters 17 19383499
2001 Mechanism of reaction of acyl phosph(on)ates with the beta-lactamase of Enterobacter cloacae P99. Biochemistry 17 11294628
1999 Structure-function studies of Ser-289 in the class C beta-lactamase from Enterobacter cloacae P99. Antimicrobial agents and chemotherapy 17 10049265
2021 Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'. Pharmaceutics 15 34959291
2019 Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1. Nucleic acids research 15 30541148
2009 CAT53 and HFE alleles in Alzheimer's disease: a putative protective role of the C282Y HFE mutation. Neuroscience letters 15 19429178
2008 PNUTS forms a trimeric protein complex with GABA(C) receptors and protein phosphatase 1. Molecular and cellular neurosciences 15 18325784
2017 Pomegranate peel extract attenuates D-galactose-induced oxidative stress and hearing loss by regulating PNUTS/PP1 activity in the mouse cochlea. Neurobiology of aging 14 28837860
2010 PNUTS knockdown potentiates the apoptotic effect of Roscovitine in breast and colon cancer cells. International journal of oncology 14 20372802
2004 Kinetics of turnover of cefotaxime by the Enterobacter cloacae P99 and GCl beta-lactamases: two free enzyme forms of the P99 beta-lactamase detected by a combination of pre- and post-steady state kinetics. Biochemistry 14 14992604
2010 Metallic nanoparticles bioassay for Enterobacter cloacae P99 beta-lactamase activity and inhibitor screening. The Analyst 13 20419253
1995 Inactivation of the Enterobacter cloacae P99 beta-lactamase by a fluorescent phosphonate: direct detection of ligand binding at the second site. Biochemistry 13 7893653
2024 The PNUTS phosphatase complex controls transcription pause release. Molecular cell 11 39603239
2013 miR-34a and the cardiomyopathy of senescence: SALT PNUTS, SALT PNUTS! Cell metabolism 11 23663732
2005 The D-methyl group in beta-lactamase evolution: evidence from the Y221G and GC1 mutants of the class C beta-lactamase of Enterobacter cloacae P99. Biochemistry 10 15895997
2002 Mechanism of inhibition of the beta-lactamase of Enterobacter cloacae P99 by 1:1 complexes of vanadate with hydroxamic acids. Biochemistry 10 11914079
2018 Downregulation of MicroRNA-4463 Attenuates High-Glucose- and Hypoxia-Induced Endothelial Cell Injury by Targeting PNUTS. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 9 30244253
2019 PNUTS mediates ionizing radiation-induced CNE-2 nasopharyngeal carcinoma cell migration, invasion, and epithelial-mesenchymal transition via the PI3K/AKT signaling pathway. OncoTargets and therapy 8 30863088
2022 Alternatively-spliced lncRNA-PNUTS promotes HCC cell EMT via regulating ZEB1 expression. Tumori 7 35139713
2018 Activation of human macrophage sodium channels regulates RNA processing to increase expression of the DNA repair protein PPP1R10. Immunobiology 7 30391100
2016 Biophysical Analysis of the N-Terminal Domain from the Human Protein Phosphatase 1 Nuclear Targeting Subunit PNUTS Suggests an Extended Transcription Factor TFIIS-Like Fold. The protein journal 7 27591855
2007 Saturation mutagenesis of Asn152 reveals a substrate selectivity switch in P99 cephalosporinase. Protein science : a publication of the Protein Society 7 18029418
1998 Cloning of a new gene (FB19) within HLA class I region. Biochemical and biophysical research communications 6 9784381
2012 Structural analysis of the Asn152Gly mutant of P99 cephalosporinase. Acta crystallographica. Section D, Biological crystallography 5 22948919
2009 Developing bifunctional beta-lactamase molecules with built-in target-recognizing module for prodrug therapy: identification of Enterobacter Cloacae P99 cephalosporinase loops suitable for randomization and phage-display selection. Journal of molecular recognition : JMR 5 19437416
2025 PP1/PNUTS phosphatase binds the restrictor complex and stimulates RNA Pol II transcription termination. Cell reports 4 40244850
2007 Overexpression of the recombinant Enterobacter cloacae P99 AmpC beta-lactamase and its mutants based on a phi105 prophage system in Bacillus subtilis. Protein expression and purification 4 17638579
2025 Overlapping and distinct functions of SPT6, PNUTS, and PCF11 in regulating transcription termination. Nucleic acids research 3 40103229
2023 Leishmania PNUTS discriminates between PP1 catalytic subunits through an RVxF-ΦΦ-F motif and polymorphisms in the PP1 C-tail and catalytic domain. The Journal of biological chemistry 3 37926279
1989 Purification of a class C A-type beta-lactamase from a derepressed strain of Enterobacter cloacae. Comparison of the wild-type and mutant enzyme with those from strains P99, 208 and GN7471. The Biochemical journal 3 2475102
2025 The Piwi-piRNA complex initiates transposon silencing via transcription termination factors PNUTS and Senataxin. Molecular cell 2 41167190
2024 Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression. Communications biology 2 38714838
2005 Molecular modeling of Henry-Michaelis and acyl-enzyme complexes between imipenem and Enterobacter cloacae P99 beta-lactamase. Chemistry & biodiversity 2 17192008
1988 Large-scale purification of the chromosomal beta-lactamase from Enterobacter cloacae P99. Journal of chromatography 2 3266632
2025 Protein Phosphatase 1 Regulatory Subunit PNUTS Prevents CENP-A Mislocalization and Chromosomal Instability. Molecular and cellular biology 1 40270285
2023 Leishmania PNUTS discriminates between PP1 catalytic subunits through a RVxF-ΦΦ-F motif and polymorphisms in the PP1 C-tail and catalytic domain. bioRxiv : the preprint server for biology 1 37790576
2025 PNUTS:PP1 recruitment to Tox4 regulates chromosomal dispersal in Drosophila germline development. Cell reports 0 40347473

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