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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

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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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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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