Affiliation:
1. Departments of Medicine (Hematology/Oncology)
2. Pediatrics (Hematology), University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
Abstract
ABSTRACT
The normal expression of human β globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with α-globin mRNA, the specific
cis
-acting determinants and
trans
-acting factors that participate in stabilizing β-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the β-globin 3′ untranslated region (3′UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by αCP/hnRNP-E, a factor that plays a critical role in stabilizing human α-globin mRNA. Mutations within the new determinant destabilize β-globin mRNA in intact cells while also ablating its 3′UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3′UTR-bound nucleolin enhances mRNA stability by optimizing αCP access to its functional binding site. This model is favored by in vitro evidence that αCP binding is enhanced both by
cis
-acting stem-destabilizing mutations and by the
trans
-acting effects of supplemental nucleolin. These studies suggest a mechanism for β-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human α-globin mRNA.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
81 articles.
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