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Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective
Crystallography, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, Berlin 13125, Germany
Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 6, Berlin 14195, Germany
* Author to whom correspondence should be addressed.
Received: 31 May 2013; in revised form: 22 July 2013 / Accepted: 25 July 2013 / Published: 9 August 2013
Abstract: Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.
Keywords: Lin28; let-7 miRNA; miRNA processing; RNA-binding protein; cold-shock domain; zinc-knuckle domain; TUTase; oncogene; stem cell
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Mayr, F.; Heinemann, U. Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective. Int. J. Mol. Sci. 2013, 14, 16532-16553.
Mayr F, Heinemann U. Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective. International Journal of Molecular Sciences. 2013; 14(8):16532-16553.
Mayr, Florian; Heinemann, Udo. 2013. "Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective." Int. J. Mol. Sci. 14, no. 8: 16532-16553.