A cytosine-rich splice regulatory determinant enforces functional processing of the human α-globin gene transcript.
Blood
; 133(21): 2338-2347, 2019 05 23.
Article
em En
| MEDLINE
| ID: mdl-30833414
ABSTRACT
The establishment of efficient and stable splicing patterns in terminally differentiated cells is critical to maintenance of specific functions throughout the lifespan of an organism. The human α-globin (hα-globin) gene contains 3 exons separated by 2 short introns. Naturally occurring α-thalassemia mutations that trigger aberrant splicing have revealed the presence of cryptic splice sites within the hα-globin gene transcript. How cognate (functional) splice sites are selectively used in lieu of these cryptic sites has remained unexplored. Here we demonstrate that the preferential selection of a cognate splice donor essential to functional splicing of the hα-globin transcript is dependent on the actions of an intronic cytosine (C)-rich splice regulatory determinant and its interacting polyC-binding proteins. Inactivation of this determinant by mutation of the C-rich element or by depletion of polyC-binding proteins triggers a dramatic shift in splice donor activity to an upstream, out-of-frame, cryptic donor. The essential role of the C-rich element in hα-globin gene expression is supported by its coevolution with the cryptic donor site in primate species. These data lead us to conclude that an intronic C-rich determinant enforces functional splicing of the hα-globin transcript, thus acting as an obligate determinant of hα-globin gene expression.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Poli C
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RNA Mensageiro
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Splicing de RNA
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Proteínas de Ligação a RNA
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Sequências Reguladoras de Ácido Ribonucleico
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Alfa-Globinas
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article