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

Andrew T. Ludlow, Mandy Sze Wong, Jerome D. Robin, Kimberly Batten, Laura Yuan, Tsung Po Lai, Nicole Dahlson, Lu Zhang, Ilgen Mender, Enzo Tedone, Mohammed E. Sayed, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number3112
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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splicing
Telomerase
Cell growth
Non-Small Cell Lung Carcinoma
lungs
cancer
Cells
Telomere Shortening
Growth
Neoplasms
telomeres
RNA-Directed DNA Polymerase
Alternative Splicing
Bioinformatics
Heterografts
Small Interfering RNA
Exons
Protein Isoforms
Genes
Computational Biology

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. / Ludlow, Andrew T.; Wong, Mandy Sze; Robin, Jerome D.; Batten, Kimberly; Yuan, Laura; Lai, Tsung Po; Dahlson, Nicole; Zhang, Lu; Mender, Ilgen; Tedone, Enzo; Sayed, Mohammed E.; Wright, Woodring E.; Shay, Jerry W.

In: Nature Communications, Vol. 9, No. 1, 3112, 01.12.2018.

Research output: Contribution to journalArticle

Ludlow, AT, Wong, MS, Robin, JD, Batten, K, Yuan, L, Lai, TP, Dahlson, N, Zhang, L, Mender, I, Tedone, E, Sayed, ME, Wright, WE & Shay, JW 2018, 'NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer', Nature Communications, vol. 9, no. 1, 3112. https://doi.org/10.1038/s41467-018-05582-x
Ludlow, Andrew T. ; Wong, Mandy Sze ; Robin, Jerome D. ; Batten, Kimberly ; Yuan, Laura ; Lai, Tsung Po ; Dahlson, Nicole ; Zhang, Lu ; Mender, Ilgen ; Tedone, Enzo ; Sayed, Mohammed E. ; Wright, Woodring E. ; Shay, Jerry W. / NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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