Molecular Biology

Regulating the Regulators

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Science  11 Aug 2006:
Vol. 313, Issue 5788, pp. 735
DOI: 10.1126/science.313.5788.735b

MicroRNAs are small noncoding RNAs that regulate gene expression in eukaryotes by targeting homologous sequences in messenger RNAs, but less is known about how the synthesis of miRNAs is regulated. To begin with, miRNA genes are transcribed by RNA polymerase II. After transcription, miRNAs undergo a complex maturation process: (i) the primary miRNA, or pri-miRNA, is cleaved by the nuclear enzyme Drosha into a stem-loop precursor called a pre-miRNA, and (ii) the pre-miRNA is exported to the cytoplasm and cleaved by Dicer into the mature 22-nucleotide miRNA.

Mouse let-7 miRNAs are strongly induced during embryonic development, and the levels of pre-miRNA and mature miRNA change coordinately. In contrast, Thompson et al. show that for several of these same let-7 miRNAs, the levels of pri-miRNAs are constant during embryogenesis, suggesting that pri-miRNA maturation is being regulated at the Drosha processing step, and that this is also true for a number of other developmentally regulated mouse miRNAs. Intriguingly, the generalized down-regulation of miRNAs in cancer may be due to a block at the Drosha processing step. Together with previous evidence that miRNA levels can be controlled at the stage of Dicer cleavage, regulating pri/pre-miRNA processing provides a further mechanism for tightly constraining the expression of developmentally potent (and thus potentially dangerous) miRNAs. — GR

Genes Dev. 20, 2202 (2006).

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