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

Ludlow, A. T., Wong, M. S., Robin, J. D., Batten, K., Yuan, L., Lai, T. P., Dahlson, N., Zhang, L., Mender, I., Tedone, E., Sayed, M. E., Wright, W. E., Shay, J. W. (August 2018) NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. Nat Commun, 9 (1). p. 3112. ISSN 2041-1723

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URL: https://www.ncbi.nlm.nih.gov/pubmed/30082712
DOI: 10.1038/s41467-018-05582-x

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Depositing User: Matthew Dunn
Date: 6 August 2018
Date Deposited: 15 Aug 2018 15:24
Last Modified: 10 Sep 2019 16:16
PMCID: PMC6079032
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37117

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