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TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes
Yukio Kawahara and Ai Mieda-Sato
Proceedings of the National Academy of Sciences of the United States of America
Vol. 109, No. 9 (February 28, 2012), pp. 3347-3352
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41506953
Page Count: 6
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Although aberrant microRNA (miRNA) expression is linked to human diseases including cancer, the mechanisms that regulate the expression of each individual miRNA remain largely unknown. TAR DNA-binding protein-43 (TDP-43) is homologous to the heterogeneous nuclear ribonucleoproteins (hnRNPs), which are involved in RNA processing, and its abnormal cellular distribution is a key feature of amyotrophic lateral sclerosis (ALS) and f rontotemporal lobar degeneration (FTLD), two neurodegenerative diseases. Here, we show that TDP-43 facilitates the production of a subset of precursor miRNAs (pre-miRNAs) by both interacting with the nuclear Drosha complex and binding directly to the relevant primary miRNAs (primiRNAs). Furthermore, cytoplasmic TDP-43, which interacts with the Dicer complex, promotes the processing of some of these premiRNAs via binding to their terminal loops. Finally, we show that involvement of TDP-43 in miRNA biogenesis is indispensable for neuronal outgrowth. These results support a previously uncharacterized role for TDP-43 in posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm.
Proceedings of the National Academy of Sciences of the United States of America © 2012 National Academy of Sciences