NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

被引：41

作者：

Sayed, Mohammed E. ^{[1
]}

Yuan, Laura ^{[2
]}

Robin, Jerome D. ^{[3
]}

Tedone, Enzo ^{[2
]}

Batten, Kimberly ^{[2
]}

Dahlson, Nicole ^{[2
]}

Wright, Woodring E. ^{[2
]}

Shay, Jerry W. ^{[2
]}

Ludlow, Andrew T. ^{[1
]}

机构：

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

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

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

来源：

ONCOGENE | 2019年 / 38卷 / 16期

关键词：

REVERSE-TRANSCRIPTASE HTERT; CATALYTIC SUBUNIT GENE; SPLICING PATTERNS; ALIGNMENT; HALLMARKS; ROLES;

D O I：

10.1038/s41388-018-0639-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alternative splicing is dysregulated in cancer cells, driving the production of isoforms that allow tumor cells to survive and continuously proliferate. Part of the reactivation of telomerase involves the splicing of hTERT transcripts to produce full-length (FL) TERT. Very few splicing factors to date have been described to interact with hTERT and promote the production of FL TERT. We recently described one such splicing factor, NOVA1, that acts as an enhancer of FL hTERT splicing, increases telomerase activity, and promotes telomere maintenance in cancer cells. NOVA1 is expressed primarily in neurons and is involved in neurogenesis. In the present studies, we describe that polypyrimidine-tract binding proteins (PTBPs), which are also typically involved in neurogenesis, are also participating in the splicing of hTERT to FL in cancer. Knockdown experiments of PTBP1 in cancer cells indicate that PTBP1 reduces hTERT FL splicing and telomerase activity. Stable knockdown of PTBP1 results in progressively shortened telomere length in H1299 and H920 lung cancer cells. RNA pulldown experiments reveal that PTBP1 interacts with hTERT pre-mRNA in a NOVA1 dependent fashion. Knockdown of PTBP1 increases the expression of PTBP2 which also interacts with NOVA1, potentially preventing the association of NOVA1 with hTERT pre-mRNA. These new data highlight that splicing in cancer cells is regulated by competition for splice sites and that combinations of splicing factors interact at cis regulatory sites on pre-mRNA transcripts. By employing hTERT as a model gene, we show the coordination of the splicing factors NOVA1 and PTBP1 in cancer by regulating telomerase that is expressed in the vast majority of cancer cell types.

引用

页码：2937 / 2952

页数：16