Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 nrb

Taiji Ito, Hirotaka Watanabe, Nobutake Yamamichi, Shunsuke Kondo, Toshio Tando, Takeshi Haraguchi, Taketoshi Mizutani, Kohei Sakurai, Shuji Fujita, Tomonori Izumi, Toshiaki Isobe, Hideo Iba

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54nrb, binds both BRG1 (Brahma-related gene 1) and Brm (Brahma), catalytic subunits of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, and also another core subunit of this complex, BAF60a. The N-terminal region of p54nrb is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54nrb binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54nrb, was also found to associate with the SWI/SNF-like complex. When sh (short hairpin) RNAs targeting Brm were retrovirally expressed in a BRG1-deficient human cell line (NCI-H1299), the resulting clones showed down-regulation of the TERT (telomerase reverse transcriptase) gene and an enhancement of ratios of exon-7-and-8-excluded TERT mRNA that encodes a β-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54nrb, PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser2 specifically colocalize at a region incorporating an alternative splicing acceptor site of TERT exon 7. These findings suggest that, at the TERT gene locus in human tumour cells containing a functional SWI/SNF complex, Brm, and possibly BRG1, in concert with p54 nrb, would initiate efficient transcription and could be involved in the subsequent splicing of TERT transcripts by accelerating exon-inclusion, which partly contributes to the maintenance of active telomerase.

Original languageEnglish
Pages (from-to)201-209
Number of pages9
JournalBiochemical Journal
Volume411
Issue number1
DOIs
Publication statusPublished - 01-04-2008
Externally publishedYes

Fingerprint

Telomerase
Genes
Sucrose
Switches
Protein Splicing
Exons
Drosophila
Polypyrimidine Tract-Binding Protein
Clone Cells
Cells
Proteins
Chromatin Assembly and Disassembly
RNA Polymerase II
Alternative Splicing
Transcription
Small Interfering RNA
Chromatin
Tumors
Catalytic Domain
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ito, Taiji ; Watanabe, Hirotaka ; Yamamichi, Nobutake ; Kondo, Shunsuke ; Tando, Toshio ; Haraguchi, Takeshi ; Mizutani, Taketoshi ; Sakurai, Kohei ; Fujita, Shuji ; Izumi, Tomonori ; Isobe, Toshiaki ; Iba, Hideo. / Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 nrb. In: Biochemical Journal. 2008 ; Vol. 411, No. 1. pp. 201-209.
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abstract = "We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54nrb, binds both BRG1 (Brahma-related gene 1) and Brm (Brahma), catalytic subunits of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, and also another core subunit of this complex, BAF60a. The N-terminal region of p54nrb is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54nrb binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54nrb, was also found to associate with the SWI/SNF-like complex. When sh (short hairpin) RNAs targeting Brm were retrovirally expressed in a BRG1-deficient human cell line (NCI-H1299), the resulting clones showed down-regulation of the TERT (telomerase reverse transcriptase) gene and an enhancement of ratios of exon-7-and-8-excluded TERT mRNA that encodes a β-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54nrb, PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser2 specifically colocalize at a region incorporating an alternative splicing acceptor site of TERT exon 7. These findings suggest that, at the TERT gene locus in human tumour cells containing a functional SWI/SNF complex, Brm, and possibly BRG1, in concert with p54 nrb, would initiate efficient transcription and could be involved in the subsequent splicing of TERT transcripts by accelerating exon-inclusion, which partly contributes to the maintenance of active telomerase.",
author = "Taiji Ito and Hirotaka Watanabe and Nobutake Yamamichi and Shunsuke Kondo and Toshio Tando and Takeshi Haraguchi and Taketoshi Mizutani and Kohei Sakurai and Shuji Fujita and Tomonori Izumi and Toshiaki Isobe and Hideo Iba",
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Ito, T, Watanabe, H, Yamamichi, N, Kondo, S, Tando, T, Haraguchi, T, Mizutani, T, Sakurai, K, Fujita, S, Izumi, T, Isobe, T & Iba, H 2008, 'Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 nrb', Biochemical Journal, vol. 411, no. 1, pp. 201-209. https://doi.org/10.1042/BJ20071075

Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 nrb. / Ito, Taiji; Watanabe, Hirotaka; Yamamichi, Nobutake; Kondo, Shunsuke; Tando, Toshio; Haraguchi, Takeshi; Mizutani, Taketoshi; Sakurai, Kohei; Fujita, Shuji; Izumi, Tomonori; Isobe, Toshiaki; Iba, Hideo.

In: Biochemical Journal, Vol. 411, No. 1, 01.04.2008, p. 201-209.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 nrb

AU - Ito, Taiji

AU - Watanabe, Hirotaka

AU - Yamamichi, Nobutake

AU - Kondo, Shunsuke

AU - Tando, Toshio

AU - Haraguchi, Takeshi

AU - Mizutani, Taketoshi

AU - Sakurai, Kohei

AU - Fujita, Shuji

AU - Izumi, Tomonori

AU - Isobe, Toshiaki

AU - Iba, Hideo

PY - 2008/4/1

Y1 - 2008/4/1

N2 - We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54nrb, binds both BRG1 (Brahma-related gene 1) and Brm (Brahma), catalytic subunits of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, and also another core subunit of this complex, BAF60a. The N-terminal region of p54nrb is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54nrb binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54nrb, was also found to associate with the SWI/SNF-like complex. When sh (short hairpin) RNAs targeting Brm were retrovirally expressed in a BRG1-deficient human cell line (NCI-H1299), the resulting clones showed down-regulation of the TERT (telomerase reverse transcriptase) gene and an enhancement of ratios of exon-7-and-8-excluded TERT mRNA that encodes a β-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54nrb, PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser2 specifically colocalize at a region incorporating an alternative splicing acceptor site of TERT exon 7. These findings suggest that, at the TERT gene locus in human tumour cells containing a functional SWI/SNF complex, Brm, and possibly BRG1, in concert with p54 nrb, would initiate efficient transcription and could be involved in the subsequent splicing of TERT transcripts by accelerating exon-inclusion, which partly contributes to the maintenance of active telomerase.

AB - We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54nrb, binds both BRG1 (Brahma-related gene 1) and Brm (Brahma), catalytic subunits of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, and also another core subunit of this complex, BAF60a. The N-terminal region of p54nrb is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54nrb binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54nrb, was also found to associate with the SWI/SNF-like complex. When sh (short hairpin) RNAs targeting Brm were retrovirally expressed in a BRG1-deficient human cell line (NCI-H1299), the resulting clones showed down-regulation of the TERT (telomerase reverse transcriptase) gene and an enhancement of ratios of exon-7-and-8-excluded TERT mRNA that encodes a β-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54nrb, PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser2 specifically colocalize at a region incorporating an alternative splicing acceptor site of TERT exon 7. These findings suggest that, at the TERT gene locus in human tumour cells containing a functional SWI/SNF complex, Brm, and possibly BRG1, in concert with p54 nrb, would initiate efficient transcription and could be involved in the subsequent splicing of TERT transcripts by accelerating exon-inclusion, which partly contributes to the maintenance of active telomerase.

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