NOVA1 Regulates HTERT Splicing and Cell Growth in Non-small Cell Lung Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Aug 8

PMID 30082712

Citations 51

Authors

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

Affiliations

Soon will be listed here.

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.

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