NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells.
A549 Cells
Alternative Splicing
/ genetics
Cell Line
Cell Line, Tumor
HCT116 Cells
HEK293 Cells
HeLa Cells
Heterogeneous-Nuclear Ribonucleoproteins
/ genetics
Humans
Neoplasms
/ genetics
Neuro-Oncological Ventral Antigen
Polypyrimidine Tract-Binding Protein
/ genetics
RNA Precursors
/ genetics
RNA Splicing
/ genetics
RNA, Messenger
/ genetics
RNA-Binding Proteins
/ genetics
Telomerase
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
02
08
2018
accepted:
04
12
2018
revised:
24
10
2018
pubmed:
21
12
2018
medline:
30
4
2019
entrez:
21
12
2018
Statut:
ppublish
Résumé
Alternative splicing is dysregulated in cancer cells, driving the production of isoforms that allow tumor cells to survive and continuously proliferate. Part of the reactivation of telomerase involves the splicing of hTERT transcripts to produce full-length (FL) TERT. Very few splicing factors to date have been described to interact with hTERT and promote the production of FL TERT. We recently described one such splicing factor, NOVA1, that acts as an enhancer of FL hTERT splicing, increases telomerase activity, and promotes telomere maintenance in cancer cells. NOVA1 is expressed primarily in neurons and is involved in neurogenesis. In the present studies, we describe that polypyrimidine-tract binding proteins (PTBPs), which are also typically involved in neurogenesis, are also participating in the splicing of hTERT to FL in cancer. Knockdown experiments of PTBP1 in cancer cells indicate that PTBP1 reduces hTERT FL splicing and telomerase activity. Stable knockdown of PTBP1 results in progressively shortened telomere length in H1299 and H920 lung cancer cells. RNA pulldown experiments reveal that PTBP1 interacts with hTERT pre-mRNA in a NOVA1 dependent fashion. Knockdown of PTBP1 increases the expression of PTBP2 which also interacts with NOVA1, potentially preventing the association of NOVA1 with hTERT pre-mRNA. These new data highlight that splicing in cancer cells is regulated by competition for splice sites and that combinations of splicing factors interact at cis regulatory sites on pre-mRNA transcripts. By employing hTERT as a model gene, we show the coordination of the splicing factors NOVA1 and PTBP1 in cancer by regulating telomerase that is expressed in the vast majority of cancer cell types.
Identifiants
pubmed: 30568224
doi: 10.1038/s41388-018-0639-8
pii: 10.1038/s41388-018-0639-8
pmc: PMC6474811
mid: NIHMS1515994
doi:
Substances chimiques
Heterogeneous-Nuclear Ribonucleoproteins
0
NOVA1 protein, human
0
Neuro-Oncological Ventral Antigen
0
PTBP1 protein, human
0
RNA Precursors
0
RNA, Messenger
0
RNA-Binding Proteins
0
Polypyrimidine Tract-Binding Protein
139076-35-0
TERT protein, human
EC 2.7.7.49
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2937-2952Subventions
Organisme : NIA NIH HHS
ID : R01 AG001228
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA197672
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA197672
Pays : United States
Organisme : NCRR NIH HHS
ID : C06 RR030414
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA124334
Pays : United States
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