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Published online July 14, 2008
doi:10.1083/jcb.200803111
The Journal of Cell Biology, Vol. 182, No. 1, 61-76
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Pawlicki et al.
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Article

 Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production

Jan M. Pawlicki1 and Joan A. Steitz2

1 Department of Pharmacology and 2 Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536

Correspondence to Joan A. Steitz: joan.steitz{at}yale.edu

MicroRNAs (miRNAs) are noncoding RNAs with important roles in regulating gene expression. In studying the earliest nuclear steps of miRNA biogenesis, we observe that primary miRNA (pri-miRNA) transcripts retained at transcription sites due to the deletion of 3'-end processing signals are converted more efficiently into precursor miRNAs (pre-miRNAs) than pri-miRNAs that are cleaved, polyadenylated, and released. Flanking exons, which also increase retention at transcription sites, likewise contribute to increased levels of intronic pri-miRNAs. Consistently, efficiently processed endogenous pri-miRNAs are enriched in chromatin-associated nuclear fractions. In contrast, pri-miRNAs that accumulate to high nuclear levels after cleavage and polyadenylation because of the presence of a viral RNA element (the ENE of the Kaposi's sarcoma–associated herpes virus polyadenylated nuclear RNA) are not efficiently processed to precursor or mature miRNAs. Exogenous pri-miRNAs unexpectedly localize to nuclear foci containing splicing factor SC35; yet these foci are unlikely to represent sites of miRNA transcription or processing. Together, our results suggest that pri-miRNA processing is enhanced by coupling to transcription.

Abbreviations used in this paper: BGH, bovine growth hormone; BIC, B cell integration cluster; CMV, cytomegalovirus; CPA, cleavage and polyadenylation; DIG, digoxygenin; EBNA, EBV nuclear antigen; EBV, Epstein Barr virus; IF, immunofluorescence; ISH; in situ hybridization; miRNA, microRNA; PolyA, polyadenylate; pre-miRNA, precursor miRNA; pre-mRNA, precursor mRNA; pri-miRNA, primary miRNA; snRNA, small nuclear RNA; SV40, simian virus 40.


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