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MicroRNA Signatures as Diagnostic and Therapeutic Targets

¹ Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, Philadelphia, PA; ² Departments of Medicine, Molecular Pharmacology & Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN.

^aAddress correspondence to this author at: 132 South 10th St., 1170 Main, Philadelphia, PA 19107. Fax 215-955-5681; e-mail scott.waldman@jefferson.edu

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MicroRNAs (miRNAs)¹ are short, noncoding RNA molecules capable of regulating gene expression at transcription and translation levels(1). Conserved throughout evolution, miRNAs participate in fundamental biologic processes including cell cycle, differentiation, development, metabolism, patterning, and aging. The human genome contains approximately 1000 miRNAs that are estimated to regulate a third of all genes. These regulatory molecules originate, by transcription of distinct genes in the noncoding portions of chromosomes, as precursor RNA molecules containing hundreds to thousands of nucleotides, which undergo distinct nuclear and cytoplasmic processing. Specifically, miRNAs originate in the nucleus as pri-miRNAs, precursors transcribed by RNA polymerase II (Fig. 1 ). Subsequently, cleavage by a ribonuclease III called Drosha and the double-stranded DNA binding protein DGCR8/Pasha generates a hairpin-shaped premiRNA. These intermediates are transported by the nuclear export factor exportin 5/Ran GTP into the cytosol, where they are processed into 19- to 25-nucleotide miRNA duplexes by the ribonuclease III Dicer, in association with the transactivation-responsive RNA-binding protein. These duplexes incorporate as the targeting core of RNA-induced silencing complexes, inducing translational inhibition by cleavage and degradation of messenger RNA . . . [Full Text of this Article]

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