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Novel nuclear hENT2 isoforms regulate cell cycle progression via controlling nucleoside transport and nuclear reservoir

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Abstract

Nucleosides participate in many cellular processes and are the fundamental building blocks of nucleic acids. Nucleoside transporters translocate nucleosides across plasma membranes although the mechanism by which nucleos(t)ides are translocated into the nucleus during DNA replication is unknown. Here, we identify two novel functional splice variants of equilibrative nucleoside transporter 2 (ENT2), which are present at the nuclear envelope. Under proliferative conditions, these splice variants are up-regulated and recruit wild-type ENT2 to the nuclear envelope to translocate nucleosides into the nucleus for incorporation into DNA during replication. Reduced presence of hENT2 splice variants resulted in a dramatic decrease in cell proliferation and dysregulation of cell cycle due to a lower incorporation of nucleotides into DNA. Our findings support a novel model of nucleoside compartmentalisation at the nuclear envelope and translocation into the nucleus through hENT2 and its variants, which are essential for effective DNA synthesis and cell proliferation.

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Abbreviations

CHX:

Cycloheximide

ER:

Endoplasmic reticulum

hCNT:

Human concentrative nucleoside transporter

hENT:

Human equilibrative nucleoside transporter

INM:

Inner nuclear membrane

NCX:

Sodium–calcium exchanger

NE:

Nuclear envelope

NMD:

Nonsense-mediated decay

NPC:

Nuclear pore complex

NT:

Nucleoside transporter

ONM:

Outer nuclear membrane

ORF:

Open reading frame

PPI:

Protein–protein interaction

PP1:

Protein phosphatase 1

PTC:

Premature termination codon

TMD:

Transmembrane domain

WT:

Wild type

References

  1. Bertoli C, Skotheim JM, de Bruin RAM (2013) Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 14:518–528. doi:10.1038/nrm3629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Golias CH, Charalabopoulos A, Charalabopoulos K (2004) Cell proliferation and cell cycle control: a mini review. Int J Clin Pract 58:1134–1141. doi:10.1111/j.1368-5031.2004.00284.x

    Article  CAS  PubMed  Google Scholar 

  3. Massagué J (2004) G1 cell-cycle control and cancer. Nature 432:298–306. doi:10.1038/nature03094

    Article  PubMed  Google Scholar 

  4. Alabert C, Groth A (2012) Chromatine replication and epigenome maintenance. Nat Rev Mol Cell Biol 13:153–167. doi:10.1038/nrm3288

    Article  CAS  PubMed  Google Scholar 

  5. Kelly TJ, Brown GW (2000) Regulation of chromosome replication. Annu Rev Biochem 69:829–880. doi:10.1146/annurev.biochem.69.1.829

    Article  CAS  PubMed  Google Scholar 

  6. McCulloch SD, Kunkel TA (2008) The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 18:148–161. doi:10.1038/cr.2008.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Anglana M, Apiou F, Bensimon A, Debatisse M (2003) Dynamics of DNA replication in mammalian somatic cells. Cell 114:385–394. doi:10.1016/S0092-8674(03)00569-5

    Article  CAS  PubMed  Google Scholar 

  8. Bester AC, Roniger M, Oren YS et al (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–446. doi:10.1016/j.cell.2011.03.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cabrita MA, Baldwin SA, Young JD, Cass CE (2002) Molecular biology and regulation of nucleoside and nucleobase transporter proteins in eukaryotes and prokaryotes. Biochem Cell Biol 80:623–638

    Article  CAS  PubMed  Google Scholar 

  10. Rose JB, Coe IR (2008) Physiology of nucleoside transporters: back to the future. Physiology (Bethesda) 23:41–48. doi:10.1152/physiol.00036.2007

    Article  CAS  Google Scholar 

  11. Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim Biophys Acta 1783:673–694. doi:10.1016/j.bbamcr.2008.01.024

    Article  CAS  PubMed  Google Scholar 

  12. Molina-Arcas M, Casado FJ, Pastor-Anglada M (2009) Nucleoside transporter proteins. Curr Vasc Pharmacol 7:426–434

    Article  CAS  PubMed  Google Scholar 

  13. dos Santos-Rodrigues A, Grañe-Boladeras N, Bicket A, Coe IR (2014) Nucleoside transporters in the purinome. Neurochem Int 73:229–237. doi:10.1016/j.neuint.2014.03.014

    Article  PubMed  Google Scholar 

  14. Young JD, Yao SYM, Baldwin JM et al (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol Aspects Med 34:529–547. doi:10.1016/j.mam.2012.05.007

    Article  CAS  PubMed  Google Scholar 

  15. Endo Y, Obata T, Murata D et al (2007) Cellular localization and functional characterization of the equilibrative nucleoside transporters of antitumor nucleosides. Cancer Sci 98:1633–1637. doi:10.1111/j.1349-7006.2007.00581.x

    Article  CAS  PubMed  Google Scholar 

  16. Griffiths M, Beaumont N, Yao SYM et al (1997) Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med 3:89–93

    Article  CAS  PubMed  Google Scholar 

  17. Williams JB, Lanahan AA (1995) A mammalian delayed-early response gene encodes HNP36, a novel, conserved nucleolar protein. Biochem Biophys Res Commun 213:325–333. doi:10.1006/bbrc.1995.2133

    Article  CAS  PubMed  Google Scholar 

  18. Crawford CR, Patel DH, Naeve C, Belt JA (1998) Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line. J Biol Chem 273:5288–5293

    Article  CAS  PubMed  Google Scholar 

  19. Mani RS, Hammond JR, Marjan JM et al (1998) Demonstration of equilibrative nucleoside transporters (hENT1 and hENT2) in nuclear envelopes of cultured human choriocarcinoma (BeWo) cells by functional reconstitution in proteoliposomes. J Biol Chem 273:30818–30825

    Article  CAS  PubMed  Google Scholar 

  20. Bjursell G, Skoog L (1979) Control of nucleotide pools in mammalian cells. Antibiot Chemother 20:78–85

    Google Scholar 

  21. Khym JX, Jones MH, Lee WH et al (1978) On the question of compartmentalization of the nucleotide pool. J Biol Chem 253:8741–8746

    CAS  PubMed  Google Scholar 

  22. Plagemann PG (1972) Nucleotide pools in Novikoff rat hepatoma cells growing in suspension culture. 3. Effects of nucleosides in medium on levels of nucleotides in separate nucleotide pools for nuclear and cytoplasmic RNA synthesis. J Cell Biol 52:131–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chang Y-F, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76:51–74. doi:10.1146/annurev.biochem.76.050106.093909

    Article  CAS  PubMed  Google Scholar 

  24. Boutz PL, Stoilov P, Li Q et al (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev 21:1636–1652. doi:10.1101/gad.1558107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Guillén-Gómez E, Pinilla-Macua I, Pérez-Torras S et al (2012) New role of the human equilibrate nucleoside transporter 1 (hENT1) in epithelial-to-mesenchymal transition in renal tubular cells. J Cell Physiol 227:1521–1528

    Article  PubMed  Google Scholar 

  26. Yao SYM, Ng AM, Sundaram M et al (2001) Transport of antiviral 3′-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol 18:161–167

    Article  CAS  PubMed  Google Scholar 

  27. Baldwin SA, Yao SYM, Hyde RJ et al (2005) Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem 280:15880–15887. doi:10.1074/jbc.M414337200

    Article  CAS  PubMed  Google Scholar 

  28. Govindarajan R, Leung GPH, Zhou M et al (2009) Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol 296:G910–G922. doi:10.1152/ajpgi.90672.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Quah BJC, Parish CR (2010) The use of carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor lymphocyte proliferation. J Vis Exp. doi:10.3791/2259

    PubMed  PubMed Central  Google Scholar 

  30. Darzynkiewicz Z, Juan G, Bedner E (2001) Determining cell cycle stages by flow cytometry. Curr Protoc Cell Biol Chapter 8:Unit 8.4. doi:10.1002/0471143030.cb0804s01

    CAS  PubMed  Google Scholar 

  31. Xaus J, Cardó M, Valledor AF et al (1999) Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity 11:103–113

    Article  CAS  PubMed  Google Scholar 

  32. Gilchrist JS, Pierce GN (1993) Identification and purification of a calcium-binding protein in hepatic nuclear membranes. J Biol Chem 268:4291–4299

    CAS  PubMed  Google Scholar 

  33. Rosner M, Schipany K, Hengstschläger M (2013) Merging high-quality biochemical fractionation with a refined flow cytometry approach to monitor nucleocytoplasmic protein expression throughout the unperturbed mammalian cell cycle. Nat Protoc 8:602–626. doi:10.1038/nprot.2013.011

    Article  PubMed  Google Scholar 

  34. Mangravite LM, Xiao G, Giacomini KM (2003) Localization of human equilibrative nucleoside transporters, hENT1 and hENT2, in renal epithelial cells. Am J Physiol Renal Physiol 284:F902–F910. doi:10.1152/ajprenal.00215.2002

    Article  CAS  PubMed  Google Scholar 

  35. Valdés R, Elferich J, Shinde U, Landfear SM (2014) Identification of the intracellular gate for a member of the equilibrative nucleoside transporter (ENT) family. J Biol Chem 289:8799–8809. doi:10.1074/jbc.M113.546960

    Article  PubMed  PubMed Central  Google Scholar 

  36. Valdés R, Vasudevan G, Conklin D, Landfear SM (2004) Transmembrane domain 5 of the LdNT1.1 nucleoside transporter is an amphipathic helix that forms part of the nucleoside translocation pathway. Biochemistry 43:6793–6802. doi:10.1021/bi049873m

    Article  PubMed  Google Scholar 

  37. Al-Ayoubi AM, Zheng H, Liu Y et al (2012) Mitogen-activated protein kinase phosphorylation of splicing factor 45 (SPF45) regulates SPF45 alternative splicing site utilization, proliferation, and cell adhesion. Mol Cell Biol 32:2880–2893. doi:10.1128/MCB.06327-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Das S, Anczuków O, Akerman M, Krainer AR (2012) Oncogenic splicing factor SRSF1 is a critical transcriptional target of Myc. Cell Rep 1:110–117. doi:10.1016/j.celrep.2011.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tazi J, Bakkour N, Stamm S (2009) Alternative splicing and disease. Biochim Biophys Acta 1792:14–26. doi:10.1016/j.bbadis.2008.09.017

    Article  CAS  PubMed  Google Scholar 

  40. Venables JP, Klinck R, Koh C et al (2009) Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 16:670–676. doi:10.1038/nsmb.1608

    Article  CAS  PubMed  Google Scholar 

  41. Stamm S, Ben-Ari S, Rafalska I et al (2005) Function of alternative splicing. Gene 344:1–20. doi:10.1016/j.gene.2004.10.022

    Article  CAS  PubMed  Google Scholar 

  42. Chiu YH, Alvarez-Baron C, Kim EY, Dryer SE (2010) Dominant-negative regulation of cell surface expression by a pentapeptide motif at the extreme COOH terminus of an Slo1 calcium-activated potassium channel splice variant. Mol Pharmacol 77:497–507. doi:10.1124/mol.109.061929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dabertrand F, Morel J-L, Sorrentino V et al (2006) Modulation of calcium signalling by dominant negative splice variant of ryanodine receptor subtype 3 in native smooth muscle cells. Cell Calcium 40:11–21. doi:10.1016/j.ceca.2006.03.008

    Article  CAS  PubMed  Google Scholar 

  44. Leung P-K, Chow KBS, Lau P-N et al (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19:1011–1022. doi:10.1016/j.cellsig.2006.11.011

    Article  CAS  PubMed  Google Scholar 

  45. Veale EL, Rees KA, Mathie A, Trapp S (2010) Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain. J Biol Chem 285:29295–29304. doi:10.1074/jbc.M110.108423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mo W, Zhang J-T (2009) Oligomerization of human ATP-binding cassette transporters and its potential significance in human disease. Expert Opin Drug Metab Toxicol 5:1049–1063. doi:10.1517/17425250903124371

    Article  CAS  PubMed  Google Scholar 

  47. Vickers MF, Mani RS, Sundaram M et al (1999) Functional production and reconstitution of the human equilibrative nucleoside transporter (hENT1) in Saccharomyces cerevisiae. Interaction of inhibitors of nucleoside transport with recombinant hENT1 and a glycosylation-defective derivative (hENT1/N48Q). Biochem J 339(Pt 1):21–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ward JL, Leung GPH, Toan S-V, Tse C-M (2003) Functional analysis of site-directed glycosylation mutants of the human equilibrative nucleoside transporter-2. Arch Biochem Biophys 411:19–26. doi:10.1016/S0003-9861(02)00718-X

    Article  CAS  PubMed  Google Scholar 

  49. Brueggemann LI, Mackie AR, Cribbs LL et al (2014) Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. J Biol Chem 289:2099–2111. doi:10.1074/jbc.M113.527820

    Article  CAS  PubMed  Google Scholar 

  50. Mary S, Fehrentz JA, Damian M et al (2013) Heterodimerization with its splice variant blocks the ghrelin receptor 1a in a non-signaling conformation: a study with a purified heterodimer assembled into lipid discs. J Biol Chem 288:24656–24665. doi:10.1074/jbc.M113.453423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Poeppel P, Abouzied MM, Völker C, Gieselmann V (2010) Misfolded endoplasmic reticulum retained subunits cause degradation of wild-type subunits of arylsulfatase A heteromers. FEBS J 277:3404–3414. doi:10.1111/j.1742-4658.2010.07745.x

    Article  CAS  PubMed  Google Scholar 

  52. Cymer F, Schneider D (2012) Oligomerization of polytopic α-helical membrane proteins: causes and consequences. Biol Chem 393:1215–1230

    Article  CAS  PubMed  Google Scholar 

  53. Kilic F, Rudnick G (2000) Oligomerization of serotonin transporter and its functional consequences. Proc Natl Acad Sci USA 97:3106–3111. doi:10.1073/pnas.060408997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Raja M (2011) The potassium channel KcsA: a model protein in studying membrane protein oligomerization and stability of oligomeric assembly? Arch Biochem Biophys 510:1–10. doi:10.1016/j.abb.2011.03.010

    Article  CAS  PubMed  Google Scholar 

  55. Torres GE (2002) Oligomerization and trafficking of the human dopamine transporter. J Biol Chem 278:2731–2739. doi:10.1074/jbc.M201926200

    Article  PubMed  Google Scholar 

  56. Johnson ZL, Cheong C-G, Lee S-Y (2012) Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 Å. Nature 483:489–493. doi:10.1038/nature10882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mauger J-P (2011) Role of the nuclear envelope in calcium signalling. Biol Cell 104:70–83. doi:10.1111/boc.201100103

    Article  PubMed  Google Scholar 

  58. Petersen OH, Gerasimenko OV, Gerasimenko JV et al (1998) The calcium store in the nuclear envelope. Cell Calcium 23:87–90

    Article  CAS  PubMed  Google Scholar 

  59. Errasti-Murugarren E, Molina-Arcas M, Casado FJ, Pastor-Anglada M (2009) A splice variant of the SLC28A3 gene encodes a novel human concentrative nucleoside transporter-3 (hCNT3) protein localized in the endoplasmic reticulum. FASEB J 23:172–182. doi:10.1096/fj.08-113902

    Article  CAS  PubMed  Google Scholar 

  60. Ledeen RW, Wu G (2007) Sodium–calcium exchangers in the nucleus: an unexpected locus and an unusual regulatory mechanism. Ann N Y Acad Sci 1099:494–506. doi:10.1196/annals.1387.057

    Article  CAS  PubMed  Google Scholar 

  61. Wu G, Xie X, Lu Z-H, Ledeen RW (2009) Sodium–calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum. Proc Natl Acad Sci USA 106:10829–10834. doi:10.1073/pnas.0903408106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xie X, Wu G, Lu Z-H, Ledeen RW (2002) Potentiation of a sodium–calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside. J Neurochem 81:1185–1195

    Article  CAS  PubMed  Google Scholar 

  63. Moffatt BA, Ashihara H (2002) Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 39:1. doi:10.1199/tab.0018

    Google Scholar 

  64. An S, Kumar R, Sheets ED, Benkovic SJ (2008) Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 320:103–106. doi:10.1126/science.1152241

    Article  CAS  PubMed  Google Scholar 

  65. Jones ME (1980) Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis. Annu Rev Biochem 49:253–279

    Article  CAS  PubMed  Google Scholar 

  66. Lenger K (1982) Characterization of six nucleoside-nucleotide phosphotransferases from the chromatin of Morris hepatoma 9121 cells by physicochemical and biochemical techniques. Int J Biochem 14:955–960

    Article  CAS  PubMed  Google Scholar 

  67. Lenger K (1982) Isolation of nucleoside phosphotransferases from chromatin of Morris hepatoma 9121 nuclei. Int J Biochem 14:53–61

    Article  CAS  PubMed  Google Scholar 

  68. Johansson M, Brismar S, Karlsson A (1997) Human deoxycytidine kinase is located in the cell nucleus. Proc Natl Acad Sci USA 94:11941–11945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sigoillot FD, Kotsis DH, Serre V et al (2005) Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. J Biol Chem 280:25611–25620. doi:10.1074/jbc.M504581200

    Article  CAS  PubMed  Google Scholar 

  70. Ulke-Lemée A, Trinkle-Mulcahy L, Chaulk S et al (2007) The nuclear PP1 interacting protein ZAP3 (ZAP) is a putative nucleoside kinase that complexes with SAM68, CIA, NF110/45, and HNRNP-G. Biochim Biophys Acta 1774:1339–1350. doi:10.1016/j.bbapap.2007.07.015

    Article  PubMed  Google Scholar 

  71. Snider J, Kittanakom S, Damjanovic D et al (2010) Detecting interactions with membrane proteins using a membrane two-hybrid assay in yeast. Nat Protoc 5:1281–1293. doi:10.1038/nprot.2010.83

    Article  CAS  PubMed  Google Scholar 

  72. Hartmann E, Fernàndez V, Moreno V et al (2008) Five-gene model to predict survival in mantle-cell lymphoma using frozen or formalin-fixed, paraffin-embedded tissue. J Clin Oncol 26:4966–4972. doi:10.1200/JCO.2007.12.0410

    Article  PubMed  Google Scholar 

  73. Bock AJ, Dong HP, Tropé CG et al (2011) Nucleoside transporters are widely expressed in ovarian carcinoma effusions. Cancer Chemother Pharmacol 69:467–475. doi:10.1007/s00280-011-1716-7

    Article  PubMed  Google Scholar 

  74. Chen C-F, Hsu E-C, Lin K-T et al (2010) Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma. Hepatology 52:1690–1701. doi:10.1002/hep.23847

    Article  CAS  PubMed  Google Scholar 

  75. Molina-Arcas M, Bellosillo B, Casado FJ et al (2003) Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood 101:2328–2334. doi:10.1182/blood-2002-07-2236

    Article  CAS  PubMed  Google Scholar 

  76. Pastor-Anglada M, Molina-Arcas M, Casado FJ et al (2004) Nucleoside transporters in chronic lymphocytic leukaemia. Leukemia 18:385–393. doi:10.1038/sj.leu.2403271

    Article  CAS  PubMed  Google Scholar 

  77. Hagiwara M (2005) Alternative splicing: a new drug target of the post-genome era. Biochim Biophys Acta 1754:324–331. doi:10.1016/j.bbapap.2005.09.010

    Article  CAS  PubMed  Google Scholar 

  78. Sumanasekera C, Watt DS, Stamm S (2008) Substances that can change alternative splice-site selection. Biochem Soc Trans 36:483–490. doi:10.1042/BST0360483

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by La Obra Social “La Caixa”, Spain (masters fellowship); Instituto de Salud Carlos III, Spain (PFIS doctoral fellowship); Ryerson University, Canada (Postdoctoral fellowship) to NGB; the Natural Science and Engineering Research Council (NSERC) of Canada; Ryerson University to IRC; the Ministry of Economy and Competitiveness (Plan Nacional de Biomedicina—MINECO), Government of Spain (SAF2011-23660 and SAF2014-52067-R); National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD) to MPA. CIBER is an initiative of Instituto de Salud Carlos III, Spain.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, 08028, Barcelona, Spain

    Natalia Grañé-Boladeras & Marçal Pastor-Anglada

  2. Oncology Program, CIBER EHD, Instituto de Salud Carlos III, 28029, Madrid, Spain

    Natalia Grañé-Boladeras & Marçal Pastor-Anglada

  3. Department of Chemistry and Biology, Ryerson University, Toronto, ON, M5B 2K3, Canada

    Natalia Grañé-Boladeras & Imogen R. Coe

  4. Research Core Facilities, Keenan Research Centre, Li Ka Shing Knowledge Institute, Saint Michael’s Hospital, Toronto, ON, M5B 1T8, Canada

    Christopher M. Spring

  5. Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada

    W. J. Brad Hanna

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  1. Natalia Grañé-Boladeras
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  2. Christopher M. Spring
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  3. W. J. Brad Hanna
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  4. Marçal Pastor-Anglada
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Correspondence to Natalia Grañé-Boladeras.

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M. Pastor-Anglada and I. R. Coe are co-senior authors.

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Grañé-Boladeras, N., Spring, C.M., Hanna, W.J.B. et al. Novel nuclear hENT2 isoforms regulate cell cycle progression via controlling nucleoside transport and nuclear reservoir. Cell. Mol. Life Sci. 73, 4559–4575 (2016). https://doi.org/10.1007/s00018-016-2288-9

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