| 18042045 |
Ito T, Watanabe H, Yamamichi N, Kondo S, Tando T, Haraguchi T, Mizutani T, Sakurai K, Fujita S, Izumi T, Isobe T, Iba H: Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54 (nrb). Biochem J. 2008 Apr 1;411(1):201-9.
We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54 (nrb), 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 p54 (nrb) is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54 (nrb) binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54 (nrb), 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 beta-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54 (nrb), PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser (2) specifically co-localize 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. |
2(0,0,0,2) |