The nuclear phosphoinositide response to stress

Figures & data

Figure 1. Nuclear PI metabolism.

Phosphatidylinositol (PtdIns) structure and nuclear PI cycle. Sites of phosphorylation on the hydroxyl groups of the inositol head are indicated with yellow stars and carbon atom numbers are shown in red. The nuclear PIs, kinases, phosphatases, and phospholipases are shown as in Tables 1 and 2. IP₃: Ins(1,4,5)P₃. PtdIns(4,5)P₂ 4-Ptase I: Type I PtdIns(4,5)P₂ 4-phosphatase.

Figure 2. Abundance of PIs in eukaryotic cells.

Numbers showing here are the estimated percentages of each PI of the total PIs in eukaryotic cells.

Table 1. Nuclear targeted PIs: types, locations, and response to cell stress

Inositol molecules	Nuclear Location	Response to cell stress
PtdIns3P	Nuclear Matrix [24], Nucleoli [22,23]	Nuclear level increased upon genotoxic stress [25], Induced generation in the nuclear matrix upon partial hepatectomy [24]
PtdIns4P	Nuclear envelope [27], Nuclear Matrix [24], Nucleoplasm [23], Nuclear Speckles [23], Nucleoli [23], Chromatin [28]	Accumulated at DNA damage sites and involved in the repair machinery [28] Induced upon hypertrophic stress in the perinuclear region to serve as the substrate for PLCε at the nuclear envelope [27]
PtdIns5P	Nuclear Matrix [29], Chromatin [29,133]	Nuclear level increased upon genotoxic and oxidative stress, reduced upon oxidative attenuation [30,31]
PtdIns(3,4)P2	Nuclear envelope [37], Nuclear speckles [35], Nucleoli [36]	Nuclear level increased upon oxidative stress [37]
PtdIns(4,5)P2	Nuclear envelope [40,44], Nuclear Matrix [23,24,95], Nucleoplasm [23], Nuclear Speckles [23,38,98], Nucleoli [23,38,40,44], Chromatin [40], Nucleoplasmic Ca^2+ store vesicles [39], Nuclear lipid islets [41]	Nuclear level increased upon genotoxic stress [25,28]; Local enrichment at DNA damage sites [25,28]; Induced generation in the nuclear speckles upon genotoxic and oxidative stress [42,43]; Induced generation in the nuclear envelope and nucleoli upon heat stress [44];
PtdIns(3,4,5)P3	Nuclear Matrix [35,45], Nucleoplasm [46], Nuclear speckles [35,98], Nucleoli [46], Chromatin [28,79]	Nuclear level increased upon genotoxic stress [25] and proliferative stimuli [45]; Induced generation in the nucleus upon oxidative stress [47] and proliferative stimuli [47]; Accumulation at DNA damage sites upon UV irradiation [28]
DAG	Nuclear envelope [27], Inner membrane [50], Nuclear lipid droplets [50], Nuclear Matrix [51]	Nuclear level increased upon hypertrophic stress [57], proliferative stimuli [56] and differentiation stimuli [56]; Synthesized by PLCε at the nuclear envelope upon hypertrophic stress [27]
Ins(1,4,5)P3	Nuclear envelope [52], Outer membrane [52], Inner membrane [52,53], Nucleoplasmic reticulum [54], Nucleoplasmic Ca^2+ store vesicles [39]	Mediating chemical-induced hypertrophy for pathological cardiomyocyte growth [58]

Figure 3. Sub-nuclear localizations of PIs, kinases, phosphatases, phospholipases and PI-binding proteins.

Demonstration of sub-nuclear localizations of PIs, kinases, phosphatases, phospholipases and PI-binding proteins as listed in Tables 1, 2, and 3. IP₃: Ins(1,4,5)P₃. PtdIns(4,5)P₂ 4-Ptase I: Type I PtdIns(4,5)P₂ 4-phosphatase.

Table 2. Nuclear PI-metabolizing enzymes, their substrates, nuclear location and response to cell stress

Nuclear PI kinases
Enzyme	Substrate	Nuclear location	Response to cell stress
PI4KIIα	PtdIns [59]	Nucleus [61], Nucleoplasmic Ca^2+ store vesicles [39]	Unknown
PI4KIIβ	PtdIns [59]	Nucleoplasmic Ca^2+ store vesicles [39]	Unknown
PI4KIIIα	PtdIns [59]	Nucleoplasm [61], Nucleoli [61,157]	Unknown
PI4KIIIβ	PtdIns [59]	Nuclear lamina-pore complexes [62], Nuclear speckles [63]	Unknown
PIPKI⍺	PtdIns4P [25]	Nuclear matrix [8], Nucleoplasm [25], Nuclear speckles [7,25,43], Nucleoli [66], Chromatin [25]	Accumulated in the nuclear speckle under oxidative stress [43]; Induced localization to DNA damage sites [25]
PIPKIɣ_i4	PtdIns4P [65]	Nuclear matrix [8], Nuclear speckles [65]	Unknown
PIPKII⍺	PtdIns5P [7]	Nuclear matrix [8], Nuclear speckles [7]	Unknown
PIPKIIβ	PtdIns5P [69]	Nuclear matrix [8], Nuclear speckles [7,32], Chromatin [69,70]	Activated for PtdIns(4,5)P2 generation and E-cadherin upregulation upon anti-cancer drug [69]; Antagonizing the genotoxic stress-induced PtdIns5P response [70]
Class I PI3K, p85⍺	-	Nucleus [47]	Increased nuclear level with considerable tyrosine phosphorylation upon oxidative stress [47]
Class I PI3K, p85β	-	Nucleus [72]	Unknown
Class I PI3K, p110⍺	PtdIns(4,5)P2 [71]	Nucleus [74], Chromatin [74]	Unknown
Class I PI3K, p110β	PtdIns(4,5)P2 [71]	Nucleoli [46], Chromatin [74]	Increased association with chromatin upon proliferative stimuli [72]; Induced accumulated in DNA damage sites [73].
Class II⍺ PI3K	PtdIns [71], PtdIns4P [71]	Nuclear speckles[75]	Unknown
Class IIβ PI3K	PtdIns [71], PtdIns4P [71]	Nuclear envelope [158], Nuclear matrix [24,76]	Induced nuclear level and activity upon proliferative stimuli [76]; Activated for PtdIns3P generation in the nucleus upon partial hepatectomy [24]
IPMK	PtdIns(4,5)P2 [79]	Chromatin [80]	Recruited to the DNA damage sites for PtdIns(3,4,5)P3 production and ATR repair machinery [28]; Induced association with p53 for transcription regulation and cell death upon genotoxic stress [80]
Nuclear PI phosphatases
PTEN	PtdIns(3,4,5)P3 [35]	Nucleoli [62], Chromatin [83,84]	Induced nuclear import, chromatin association, and Rad52 interaction for DNA damage repair upon genotoxic and oxidative stress [84]
SHIP1	PtdIns(3,4,5)P3 [36]	Nucleoli [36]	Induced accumulation and association with p53 in nucleoli upon ER stress [36]
SHIP2	PtdIns(3,4,5)P3 [35], PtdIns(4,5)P2 [91]	Nuclear speckles [35,91]	Unknown
Type I PtdIns(4,5)P2 4-phosphatase	PtdIns(4,5)P2 [92]	Nucleus [92]	Translocated into the nucleus upon genotoxic stress [92]
Nuclear phospholipases
PLCβ1	PtdIns(4,5)P2 [56]	Nuclear matrix [93], Nuclear speckles [55]	Activated for the generation of DAG from PtdIns(4,5)P2 upon proliferative stimuli [56]; Protected cells from oxidative stress by inducing c-fos mRNA generation [94]
PLCδ1	PtdIns(4,5)P2 [95]	Nuclear matrix [95]	Translocated to the nucleus upon cell cycle arresting [95]
PLCδ4	PtdIns(4,5)P2 [96]	Nucleus [96]	Unknown

Table 3. Nuclear PI-binding proteins, their interacting PIs, associated PI enzymes, nuclear location, response to cell stress and functions

PI-binding proteins	Binding PI	Associated PI enzymes	Nuclear location	Stress response	Function
Aly	PtdIns(4,5)P2 [98], PtdIns(3,4,5)P3 [98]	IPMK [98,99]	Nucleoplasm [98], Nuclear speckle [98]	Unknown	mRNA export [98]
BASP1	PtdIns(4,5)P2 [100]	Unknown	Chromatin [100]	Sequestration abrin toxin in the nucleus [102]	Transcriptional regulation [100] and toxin resistance [102]
BRG1	PtdIns(4,5)P2 [107]	Unknown	Chromatin [103], Nuclear Matrix [107]	Potential roles in DNA damage repair, oxidative and metabolic stress [104–106]	Chromatin modification and transcriptional regulation [107,108]
EBP1	PtdIns(3,4,5)P3 [46]	PI3KI-p110β [46]	Nucleoli [46,159]	Induced sumoylation and nucleolar distribution upon genotoxic stress [159]	Post-translational modification and transcriptional regulation [159]
Fibrillarin	PtdIns(4,5)P2 [110]	Unknown	Nucleoli [111]	Reduced nucleolar level upon bacterial infection, heat shock and chemical treatment [111,113].	Configuration change [102] and transcriptional regulation [110]
ING2	PtdIns5P [29,92]	PIPKIIβ [29], Type I PtdIns(4,5)P2 4-phosphatase [92]	Nuclear Matrix [29], Chromatin [29,31]	Increased nuclear level, PtdIns5P binding, chromatin localization, regulation of p53 acetylation and apoptotic pathway upon genotoxic/oxidative stress [31,92,114]	Chromatin modification, transcriptional regulation, and stabilizing p53 [29,31,92,114]
NPM1	PtdIns(3,4,5)P3 [119]	PTEN [119], SHIP [119]	Nucleoli [115] Nucleoplasm [115]	Translocated from nucleoli to nucleoplasm upon genotoxic and viral stress [117]	Anti-apoptotic function [119] and stabilizing p53 [117]
p53	PtdIns(4,5)P2 [25]	PIPKI⍺ [25], IPMK [80], PTEN [87], SHIP1 [36]	Nucleoplasm [25], Nuclear speckles [25], Chromatin [25,143]	Induced nuclear level upon genotoxic/oxidative stress, hypoxia and oncogene activation [25,142–144]; Induced association with PtdIns(4,5)P2/PIPKI⍺/HSP27 upon genotoxic/oxidative stress [25]; Recruited to the nucleoplasm, nuclear speckles and DNA damage sites upon genotoxic stress [25]	Transcriptional regulation [143], stabilizing p53, and DNA damage repair [25]
PHF8	PtdIns(4,5)P2 [122]	Unknown	Chromatin [122]	Induced nuclear level upon genotoxic stress [123]	Transcriptional regulation [122] and cell proliferation [123]
SAP30/ SAP30L	PtdIns3P [124], PtdIns4P [124], PtdIns5P [124]	Unknown	Nucleoli [125], Chromatin [124]	Relocating from chromatin to cytoplasm and reduced repression activity upon oxidative stress [124]	Protein translocation, chromatin modification, and transcriptional regulation [124]
SF-1	PtdIns(4,5)P2 [127], PtdIns(3,4,5)P3 [127]	IPMK [79], PTEN [79]	Chromatin [79]	Protective roles under restrain, food deprivation, inflammatory inducer [128]; Induced accumulation at DNA damage sites [28].	Transcriptional regulation and DNA damage repair [28,127]; Adrenal development and stress response [128]
Star-PAP	PtdIns(4,5)P2 [43]	PIPKI⍺ [43]	Nuclear speckles [43]	Induced activity, association with PIPKIα/PtdIns(4,5)P2 in nuclear speckles upon genotoxic and oxidative stress [42,43,87,141^]	3′-end processing and post-transcriptional regulation [42,43,87,141]
Syntenin-2	PtdIns(4,5)P2 [129]	Unknown	Nucleoplasm [160], Nuclear speckles [129], Nucleoli [129]	Unknown	Maintain nuclear PtdIns(4,5)P2 pattern and contributes to cell division and survival [129]
TAF3	PtdIns5P [70]	PIPKIIβ [70]	Chromatin [70]	Enhanced interaction with PtdIns5P and transcriptional regulation upon genotoxic stress [70]	Transcriptional regulation and cell differentiation [70]
UHRF1	PtdIns(5)P [133]	Unknown	Chromatin [133] (Pericentric heterochromatin [130], Euchromatin [131,132])	Recruited to DNA damage sites [134], Protective role upon oxidative stress [135]	Chromatin modification, DNA damage repair, and transcriptional regulation [134,135]

Figure 4. Schematic illustration of nuclear PI signaling in response to cellular stress.

In response to cellular stress, the levels of nuclear PI are altered and conversions are induced due to activation of different PI-metabolizing enzymes. Through direct interaction with downstream PI-binding proteins, the PI signals are transduced into changes in cellular functions.

Sindic A, Aleksandrova A, Fields AP, et al. Presence and activation of nuclear phosphoinositide 3-kinase C2beta during compensatory liver growth. J Biol Chem. 2001;276:17754–17761.

 PubMed Web of Science ®Google Scholar

Gillooly DJ, Morrow IC, Lindsay M, et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. Embo J. 2000;19:4577–4588.

 PubMed Web of Science ®Google Scholar

Kalasova I, Faberova V, Kalendova A, et al. Tools for visualization of phosphoinositides in the cell nucleus. Histochem Cell Biol. 2016;145:485–496.

 PubMed Web of Science ®Google Scholar

Choi S, Chen M, Cryns VL, et al. A nuclear phosphoinositide kinase complex regulates p53. Nat Cell Biol. 2019;21:462–475.

 PubMed Web of Science ®Google Scholar

Zhang L, Malik S, Pang J, et al. Phospholipase Cepsilon hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy. Cell. 2013;153:216–227.

 PubMed Web of Science ®Google Scholar

Wang YH, Hariharan A, Bastianello G, et al. DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. Nat Commun. 2017;8:2118.

 PubMed Web of Science ®Google Scholar

Gozani O, Karuman P, Jones DR, et al. The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell. 2003;114:99–111.

 PubMed Web of Science ®Google Scholar

Gelato KA, Tauber M, Ong MS, et al. Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol Cell. 2014;54:905–919.

 PubMed Web of Science ®Google Scholar

Jones DR, Bultsma Y, Keune WJ, et al. Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell. 2006;23:685–695.

 PubMed Web of Science ®Google Scholar

Bua DJ, Martin GM, Binda O, et al. Nuclear phosphatidylinositol-5-phosphate regulates ING2 stability at discrete chromatin targets in response to DNA damage. Sci Rep. 2013;3:2137.

 PubMed Web of Science ®Google Scholar

Yokogawa T, Nagata S, Nishio Y, et al. Evidence that 3 ‘-phosphorylated polyphosphoinositides are generated at the nuclear surface: use of immunostaining technique with monoclonal antibodies specific for PI 3,4-P-2. Febs Lett. 2000;473:222–226.

 PubMed Web of Science ®Google Scholar

Deleris P, Bacqueville D, Gayral S, et al. SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles. J Biol Chem. 2003;278:38884–38891.

 PubMed Web of Science ®Google Scholar

Ehm P, Nalaskowski MM, Wundenberg T, et al. The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies. Nucleus. 2015;6:154–164.

 PubMed Web of Science ®Google Scholar

Watt SA, Kular G, Fleming IN, et al. Subcellular localization of phosphatidylinositol 4,5-bisphosphate using the pleckstrin homology domain of phospholipase C delta1. Biochem J. 2002;363:657–666.

 PubMed Web of Science ®Google Scholar

Mishkind M, Vermeer JE, Darwish E, et al. Heat stress activates phospholipase D and triggers PIP accumulation at the plasma membrane and nucleus. Plant J. 2009;60:10–21.

 PubMed Web of Science ®Google Scholar

Stallings JD, Tall EG, Pentyala S, et al. Nuclear translocation of phospholipase C-delta(1) is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2005;280:22060–22069.

 PubMed Web of Science ®Google Scholar

Osborne SL, Thomas CL, Gschmeissner S, et al. Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing. J Cell Sci. 2001;114:2501–2511.

 PubMed Web of Science ®Google Scholar

Okada M, Jang SW, Ye K. Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY. Proc Natl Acad Sci U S A. 2008;105:8649–8654.

 PubMed Web of Science ®Google Scholar

Yoo SH, Huh YH, Huh SK, et al. Localization and projected role of phosphatidylinositol 4-kinases IIalpha and IIbeta in inositol 1,4,5-trisphosphate-sensitive nucleoplasmic Ca(2)(+) store vesicles. Nucleus. 2014;5:341–351.

 PubMed Web of Science ®Google Scholar

Sobol M, Krausova A, Yildirim S, et al. Nuclear phosphatidylinositol 4,5-bisphosphate islets contribute to efficient RNA polymerase II-dependent transcription. J Cell Sci. 2018;131:8.

 Web of Science ®Google Scholar

Li W, Laishram RS, Ji Z, et al. Star-PAP control of BIK expression and apoptosis is regulated by nuclear PIPKIalpha and PKCdelta signaling. Mol Cell. 2012;45:25–37.

 PubMed Web of Science ®Google Scholar

Mellman DL, Gonzales ML, Song C, et al. A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs. Nature. 2008;451:1013–1017.

 PubMed Web of Science ®Google Scholar

Lindsay Y, McCoull D, Davidson L, et al. Localization of agonist-sensitive PtdIns(3,4,5)P3 reveals a nuclear pool that is insensitive to PTEN expression. J Cell Sci. 2006;119:5160–5168.

 PubMed Web of Science ®Google Scholar

Karlsson T, Altankhuyag A, Dobrovolska O, et al. A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction. Biochem J. 2016;473:2033–2047.

 PubMed Web of Science ®Google Scholar

Blind RD, Suzawa M, Ingraham HA. Direct modification and activation of a nuclear receptor-PIP(2) complex by the inositol lipid kinase IPMK. Sci Signal. 2012;5:ra44.

 PubMed Web of Science ®Google Scholar

Tanaka K, Horiguchi K, Yoshida T, et al. Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus. J Biol Chem. 1999;274:3919–3922.

 PubMed Web of Science ®Google Scholar

Romanauska A, Kohler A. The inner nuclear membrane is a metabolically active territory that generates nuclear lipid droplets. Cell. 2018;174:700-+.

 PubMed Web of Science ®Google Scholar

Payrastre B, Nievers M, Boonstra J, et al. A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase-C in the nuclear matrix. J Biol Chem. 1992;267:5078–5084.

 PubMed Web of Science ®Google Scholar

Zhang H, Shao Z, Alibin CP, et al. Liganded peroxisome proliferator-activated receptors (PPARs) preserve nuclear histone deacetylase 5 levels in endothelin-treated Sprague-Dawley rat cardiac myocytes. PLoS One. 2014;9:e115258.

 PubMed Web of Science ®Google Scholar

Neri LM, Bortul R, Borgatti P, et al. Proliferating or differentiating stimuli act on different lipid-dependent signaling pathways in nuclei of human leukemia cells. Mol Biol Cell. 2002;13:947–964.

 PubMed Web of Science ®Google Scholar

Zima AV, Bare DJ, Mignery GA, et al. IP3-dependent nuclear Ca2+ signalling in the mammalian heart. J Physiol. 2007;584:601–611.

 PubMed Web of Science ®Google Scholar

Humbert JP, Matter N, Artault JC, et al. Inositol 1,4,5-trisphosphate receptor is located to the inner nuclear membrane vindicating regulation of nuclear calcium signaling by inositol 1,4,5-trisphosphate. Discrete distribution of inositol phosphate receptors to inner and outer nuclear membranes (vol 271, pg 478, 1996). J Biol Chem. 1996;271:5287.

 Web of Science ®Google Scholar

Echevarria W, Leite MF, Guerra MT, et al. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat Cell Biol. 2003;5:440–446.

 PubMed Web of Science ®Google Scholar

Arantes LAM, Aguiar CJ, Amaya MJ, et al. Nuclear inositol 1,4,5-trisphosphate is a necessary and conserved signal for the induction of both pathological and physiological cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2012;53:475–486.

 PubMed Web of Science ®Google Scholar

Balla A, Balla T. Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol. 2006;16:351–361.

 PubMed Web of Science ®Google Scholar

Kakuk A, Friedlander E, Vereb G Jr., et al. Nucleolar localization of phosphatidylinositol 4-kinase PI4K230 in various mammalian cells. Cytometry A. 2006;69:1174–1183.

 PubMedGoogle Scholar

Kakuk A, Friedlander E, Vereb G Jr., et al. Nuclear and nucleolar localization signals and their targeting function in phosphatidylinositol 4-kinase PI4K230. Exp Cell Res. 2008;314:2376–2388.

 PubMed Web of Science ®Google Scholar

de Graaf P, Klapisz EE, Schulz TK, et al. Nuclear localization of phosphatidylinositol 4-kinase beta. J Cell Sci. 2002;115:1769–1775.

 PubMed Web of Science ®Google Scholar

Szivak I, Lamb N, Heilmeyer LM. Subcellular localization and structural function of endogenous phosphorylated phosphatidylinositol 4-kinase (PI4K92). J Biol Chem. 2006;281:16740–16749.

 PubMed Web of Science ®Google Scholar

Barlow CA, Laishram RS, Anderson RA. Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol. 2010;20:25–35.

 PubMed Web of Science ®Google Scholar

Boronenkov IV, Loijens JC, Umeda M, et al. Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol Biol Cell. 1998;9:3547–3560.

 PubMed Web of Science ®Google Scholar

Chakrabarti R, Sanyal S, Ghosh A, et al. Phosphatidylinositol-4-phosphate 5-kinase 1alpha modulates ribosomal RNA gene Silencing through its interaction with histone H3 lysine 9 trimethylation and heterochromatin protein HP1-alpha. J Biol Chem. 2015;290:20893–20903.

 PubMed Web of Science ®Google Scholar

Schill NJ, Anderson RA. Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. Biochem J. 2009;422:473–482.

 PubMed Web of Science ®Google Scholar

Kouchi Z, Fujiwara Y, Yamaguchi H, et al. Phosphatidylinositol 5-phosphate 4-kinase type II beta is required for vitamin D receptor-dependent E-cadherin expression in SW480 cells. Biochem Biophys Res Commun. 2011;408:523–529.

 PubMed Web of Science ®Google Scholar

Bunce MW, Boronenkov IV, Anderson RA. Coordinated activation of the nuclear ubiquitin ligase Cul3-SPOP by the generation of phosphatidylinositol 5-phosphate. J Biol Chem. 2008;283:8678–8686.

 PubMed Web of Science ®Google Scholar

Stijf-Bultsma Y, Sommer L, Tauber M, et al. The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output. Mol Cell. 2015;58:453–467.

 PubMed Web of Science ®Google Scholar

Kumar A, Redondo-Munoz J, Perez-Garcia V, et al. Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival. Mol Cell Biol. 2011;31:2122–2133.

 PubMed Web of Science ®Google Scholar

Jean S, Kiger AA. Classes of phosphoinositide 3-kinases at a glance. J Cell Sci. 2014;127:923–928.

 PubMed Web of Science ®Google Scholar

Marques M, Kumar A, Poveda AM, et al. Specific function of phosphoinositide 3-kinase beta in the control of DNA replication. Proc Natl Acad Sci U S A. 2009;106:7525–7530.

 PubMed Web of Science ®Google Scholar

Kumar A, Fernandez-Capetillo O, Carrera AC. Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair. Proc Natl Acad Sci U S A. 2010;107:7491–7496.

 PubMed Web of Science ®Google Scholar

Didichenko SA, Thelen M. Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles. J Biol Chem. 2001;276:48135–48142.

 PubMed Web of Science ®Google Scholar

Visnjic D, Crljen V, Curic J, et al. The activation of nuclear phosphoinositide 3-kinase C2beta in all-trans-retinoic acid-differentiated HL-60 cells. Febs Lett. 2002;529:268–274.

 PubMed Web of Science ®Google Scholar

Banfic H, Visnjic D, Mise N, et al. Epidermal growth factor stimulates translocation of the class II phosphoinositide 3-kinase PI3K-C2beta to the nucleus. Biochem J. 2009;422:53–60.

 PubMed Web of Science ®Google Scholar

Xu R, Sen N, Paul BD, et al. Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death. Sci Signal. 2013;6:ra22.

 PubMed Web of Science ®Google Scholar

Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128:157–170.

 PubMed Web of Science ®Google Scholar

Choi BH, Chen Y, Dai W. Chromatin PTEN is involved in DNA damage response partly through regulating Rad52 sumoylation. Cell Cycle. 2013;12:3442–3447.

 PubMed Web of Science ®Google Scholar

Elong Edimo W, Derua R, Janssens V, et al. Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability. Biochem J. 2011;439:391–401.

 PubMed Web of Science ®Google Scholar

Zou J, Marjanovic J, Kisseleva MV, et al. Type I phosphatidylinositol-4, 5-bisphosphate 4-phosphatase regulates stress-induced apoptosis. Proc Natl Acad Sci U S A. 2007;104:16834–16839.

 PubMed Web of Science ®Google Scholar

Cocco L, Rubbini S, Manzoli L, et al. Inositides in the nucleus: presence and characterisation of the isozymes of phospholipase beta family in NIH 3T3 cells. Biochim Biophys Acta. 1999;1438:295–299.

 PubMed Web of Science ®Google Scholar

Tabellini G, Bortul R, Santi S, et al. Diacylglycerol kinase-theta is localized in the speckle domains of the nucleus. Exp Cell Res. 2003;287:143–154.

 PubMed Web of Science ®Google Scholar

Lee YH, Kim SY, Kim JR, et al. Overexpression of phospholipase Cbeta-1 protects NIH3T3 cells from oxidative stress-induced cell death. Life Sci. 2000;67:827–837.

 PubMed Web of Science ®Google Scholar

Kunrath-Lima M, de Miranda MC, Ferreira ADF, et al. Phospholipase C delta 4 (PLCdelta4) is a nuclear protein involved in cell proliferation and senescence in mesenchymal stromal stem cells. Cell Signal. 2018;49:59–67.

 PubMed Web of Science ®Google Scholar

Wickramasinghe VO, Savill JM, Chavali S, et al. Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Mol Cell. 2013;51:737–750.

 PubMed Web of Science ®Google Scholar

Toska E, Campbell HA, Shandilya J, et al. Repression of transcription by WT1-BASP1 requires the myristoylation of BASP1 and the PIP2-dependent recruitment of histone deacetylase. Cell Rep. 2012;2:462–469.

 PubMed Web of Science ®Google Scholar

Gadadhar S, Bora N, Tiwari V, et al. Sequestration of the abrin A chain to the nucleus by BASP1 increases the resistance of cells to abrin toxicity. Biochem J. 2014;458:375–385.

 PubMed Web of Science ®Google Scholar

Zhao K, Wang W, Rando OJ, et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell. 1998;95:625–636.

 PubMed Web of Science ®Google Scholar

Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv. 2015;1:e1500447.

 PubMed Web of Science ®Google Scholar

Khan P, Drobic B, Perez-Cadahia B, et al. Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction. PLoS One. 2013;8:e63189.

 PubMed Web of Science ®Google Scholar

Porter EG, Dhiman A, Chowdhury B, et al. PBRM1 regulates stress response in epithelial cells. iScience. 2019;15:196–210.

 PubMed Web of Science ®Google Scholar

Rando OJ, Zhao K, Janmey P, et al. Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex. Proc Natl Acad Sci U S A. 2002;99:2824–2829.

 PubMed Web of Science ®Google Scholar

Oh SM, Liu Z, Okada M, et al. Ebp1 sumoylation, regulated by TLS/FUS E3 ligase, is required for its anti-proliferative activity. Oncogene. 2010;29:1017–1030.

 PubMed Web of Science ®Google Scholar

Yildirim S, Castano E, Sobol M, et al. Involvement of phosphatidylinositol 4,5-bisphosphate in RNA polymerase I transcription. J Cell Sci. 2013;126:2730–2739.

 PubMed Web of Science ®Google Scholar

Tiku V, Kew C, Mehrotra P, et al. Nucleolar fibrillarin is an evolutionarily conserved regulator of bacterial pathogen resistance. Nat Commun. 2018;9(1):3607.

 Web of Science ®Google Scholar

Kodiha M, Banski P, Stochaj U. Computer-based fluorescence quantification: a novel approach to study nucleolar biology. BMC Cell Biol. 2011;12:25.

 PubMedGoogle Scholar

Nagashima M, Shiseki M, Miura K, et al. DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. Proc Natl Acad Sci U S A. 2001;98:9671–9676.

 PubMed Web of Science ®Google Scholar

Ahn JY, Liu X, Cheng D, et al. Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. Mol Cell. 2005;18:435–445.

 PubMed Web of Science ®Google Scholar

Lindstrom MS. NPM1/B23: A multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int. 2011;2011:195209.

 PubMedGoogle Scholar

Kurki S, Peltonen K, Latonen L, et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell. 2004;5:465–475.

 PubMed Web of Science ®Google Scholar

Freeman DJ, Li AG, Wei G, et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell. 2003;3:117–130.

 PubMed Web of Science ®Google Scholar

Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14:359–370.

 PubMed Web of Science ®Google Scholar

Dai C, Gu W. p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med. 2010;16:528–536.

 PubMed Web of Science ®Google Scholar

Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015;16:393–405.

 PubMed Web of Science ®Google Scholar

Ulicna L, Kalendova A, Kalasova I, et al. PIP2 epigenetically represses rRNA genes transcription interacting with PHF8. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863:266–275.

 PubMed Web of Science ®Google Scholar

Wang Q, Ma S, Song N, et al. Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. J Clin Invest. 2016;126:2205–2220.

 PubMed Web of Science ®Google Scholar

Viiri KM, Janis J, Siggers T, et al. DNA-binding and -bending activities of SAP30L and SAP30 are mediated by a zinc-dependent module and monophosphoinositides. Mol Cell Biol. 2009;29:342–356.

 PubMed Web of Science ®Google Scholar

Viiri KM, Korkeamaki H, Kukkonen MK, et al. SAP30L interacts with members of the Sin3A corepressor complex and targets Sin3A to the nucleolus. Nucleic Acids Res. 2006;34:3288–3298.

 PubMed Web of Science ®Google Scholar

Blind RD, Sablin EP, Kuchenbecker KM, et al. The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1. Proc Natl Acad Sci U S A. 2014;111:15054–15059.

 PubMed Web of Science ®Google Scholar

Bland ML, Jamieson CA, Akana SF, et al. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci U S A. 2000;97:14488–14493.

 PubMed Web of Science ®Google Scholar

Laishram RS, Barlow CA, Anderson RA. CKI isoforms α and ε regulate star-PAP target messages by controlling star-PAP poly(A) polymerase activity and phosphoinositide stimulation. Nucleic Acids Res. 2011;39:7961–7973.

 PubMed Web of Science ®Google Scholar

Mortier E, Wuytens G, Leenaerts I, et al. Nuclear speckles and nucleoli targeting by PIP2-PDZ domain interactions. Embo J. 2005;24:2556–2565.

 PubMed Web of Science ®Google Scholar

Geeraerts A, Hsiu-Fang F, Zimmermann P, et al. The characterization of the nuclear dynamics of syntenin-2, a PIP2 binding PDZ protein. Cytometry A. 2013;83:866–875.

 PubMed Web of Science ®Google Scholar

Liu XL, Gao QQ, Li PS, et al. UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat Commun. 2013;4:1563.

 Web of Science ®Google Scholar

Bronner C, Fuhrmann G, Chedin FL, et al. UHRF1 links the histone code and DNA methylation to ensure faithful epigenetic memory inheritance. Genet Epigenet. 2010;2009:29–36.

 PubMedGoogle Scholar

Wang F, Yang YZ, Shi CZ, et al. UHRF1 promotes cell growth and metastasis through repression of p16(ink4a) in colorectal cancer. Ann Surg Oncol. 2012;19:2753–2762.

 PubMed Web of Science ®Google Scholar

Tian YY, Paramasivam M, Ghosal G, et al. UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold. Cell Rep. 2015;10:1957–1966.

 PubMed Web of Science ®Google Scholar

Abu-Alainin W, Gana T, Liloglou T, et al. UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis. J Pathol. 2016;238:423–433.

 PubMed Web of Science ®Google Scholar