Novel nuclear hENT2 isoforms regulate cell cycle progression via controlling nucleoside transport and nuclear reservoir.
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.
Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, 08028, Barcelona, Spain. nataliagrane@ryerson.ca.|Oncology Program, CIBER EHD, Instituto de Salud Carlos III, 28029, Madrid, Spain. nataliagrane@ryerson.ca.|Department of Chemistry and Biology, Ryerson University, Toronto, ON, M5B 2K3, Canada. nataliagrane@ryerson.ca.
Natalia
N
Grañé-Boladeras
Research Core Facilities, Keenan Research Centre, Li Ka Shing Knowledge Institute, Saint Michael's Hospital, Toronto, ON, M5B 1T8, Canada.
Christopher M
CM
Spring
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
W J Brad
WJ
Hanna
Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, 08028, Barcelona, Spain.|Oncology Program, CIBER EHD, Instituto de Salud Carlos III, 28029, Madrid, Spain.
Marçal
M
Pastor-Anglada
Department of Chemistry and Biology, Ryerson University, Toronto, ON, M5B 2K3, Canada.
Imogen R
IR
Coe
D017398:Alternative Splicing / Q000235:genetics; D001692:Biological Transport; D002453:Cell Cycle / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009685:Nuclear Envelope / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism*; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D033722:Equilibrative-Nucleoside Transporter 2; D009705:Nucleosides; D020033:Protein Isoforms; C438654:SLC29A2 protein, human; D013936:Thymidine
Cell cycle regulation; DNA synthesis; ENT2; HNP36; Nucleoside metabolism; Nucleoside transporters; SLC29A2