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Nat Commun. 2018 Aug 6;9(1):3112. doi: 10.1038/s41467-018-05582-x.

NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer.

Author information

1
Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. atludlow@umich.edu.
2
School of Kinesiology, University of Michigan, 401 Washtenaw Ave., Ann Arbor, MI, 48109, USA. atludlow@umich.edu.
3
Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
4
Cold Spring Harbor Laboratories, One Bungtown Road, Cold Spring Harbor, New York, NY, 11724, USA.
5
Aix-Marseille University, Marseille Medical Genetics (MMG), UMR125, Marseille, 13385, France.
6
School of Kinesiology, University of Michigan, 401 Washtenaw Ave., Ann Arbor, MI, 48109, USA.

Abstract

Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer.

PMID:
30082712
PMCID:
PMC6079032
DOI:
10.1038/s41467-018-05582-x
[Indexed for MEDLINE]
Free PMC Article

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