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

被引：66

作者：

Ludlow, Andrew T. ^{[1
,2
]}

Wong, Mandy Sze ^{[1
,3
]}

Robin, Jerome D. ^{[1
,4
]}

Batten, Kimberly ^{[1
]}

Yuan, Laura ^{[1
]}

Lai, Tsung-Po ^{[1
]}

Dahlson, Nicole ^{[1
]}

Zhang, Lu ^{[1
]}

Mender, Ilgen ^{[1
]}

Tedone, Enzo ^{[1
]}

Sayed, Mohammed E. ^{[1
,2
]}

Wright, Woodring E. ^{[1
]}

Shay, Jerry W. ^{[1
]}

机构：

[1] UT Southwestern Med Ctr, Dept Cell Biol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[2] Univ Michigan, Sch Kinesiol, 401 Washtenaw Ave, Ann Arbor, MI 48109 USA

[3] Cold Spring Harbor Labs, One Bungtown Rd, New York, NY 11724 USA

[4] Aix Marseille Univ, MMG, UMR125, F-13385 Marseille, France

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

RNA-BINDING PROTEIN; INHIBITS TELOMERASE ACTIVITY; COLORECTAL-CANCER; HNRNP A1; TUMOR SUPPRESSORS; EPITHELIAL-CELLS; IMMORTAL CELLS; MUTATIONS; DISEASE; GENE;

D O I：

10.1038/s41467-018-05582-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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