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A Nucleolin-Binding 3' Untranslated Region Element Stabilizes ß-Globin mRNA In Vivo

Departments of Medicine (Hematology/Oncology),¹ Pediatrics (Hematology), University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania²

Received 6 July 2005/ Returned for modification 19 August 2005/ Accepted 14 December 2005

The normal expression of human ß globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with -globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing ß-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the ß-globin 3' untranslated region (3'UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by CP/hnRNP-E, a factor that plays a critical role in stabilizing human -globin mRNA. Mutations within the new determinant destabilize ß-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 CP access to its functional binding site. This model is favored by in vitro evidence that CP 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 ß-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human -globin mRNA.

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