A nucleolin-binding 3' untranslated region element stabilizes beta-globin mRNA in vivo.
The normal expression of human beta globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with alpha-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing beta-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the beta-globin 3' untranslated region (3'UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by alphaCP/hnRNP-E, a factor that plays a critical role in stabilizing human alpha-globin mRNA. Mutations within the new determinant destabilize beta-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 alphaCP access to its functional binding site. This model is favored by in vitro evidence that alphaCP 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 beta-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human alpha-globin mRNA.
Jiang
Yong
Y
Department of Medicine (Hematology/Oncology), Abramson University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Xu
Xiang-Sheng
XS
Russell
J Eric
JE
D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D000097796:Nucleolin
D020413:3' Untranslated Regions; D005914:Globins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin