Mad about U: regulating the let7 pre-miRNA

Over 60% of the human protein-coding genes are regulated by microRNAs (miRNAs), underscoring their critical role in many, if not most, biological processes. We are interested in the regulation of a particular developmental miRNA, let-7. Let-7 regulates proliferation genes such as MYC, HMGA2, and Ras and thus plays an important role in stem-cell differentiation and acts as a tumor suppressor. In stem cells, the pluripotent factor, Lin28, binds to precursor let-7 (pre-let-7) hairpins, triggering the 3’ oligouridylation activity of TUT4/7. The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by the exonuclease Dis3L2. Genetic disruption of DIS3L2 is the primary cause of Perlman syndrome, a congenital disorder leading to fetal overgrowth and increased susceptibility to Wilms’ tumor development. In somatic cells, in the absence of Lin28, TUT4/7 promotes let-7 biogenesis by catalyzing single uridine addition to a subset of pre-let-7 miRNAs. I will present some of our work on the molecular mechanisms underlying this fascinating regulatory system, from biogenesis by the Microprocessor, to destruction by Dis3L2.

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Host: Ivet Bahar