Coupled RNA Processing and Transcription of Intergenic Primary MicroRNAs

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2009 Aug 12

PMID 19667074

Citations 69

Authors

Monica Ballarino

Francesca Pagano

Erika Girardi

Mariangela Morlando

Davide Cacchiarelli

Marcella Marchioni

Nicholas J Proudfoot

Irene Bozzoni

Affiliations

Soon will be listed here.

Abstract

The first step in microRNA (miRNA) biogenesis occurs in the nucleus and is mediated by the Microprocessor complex containing the RNase III-like enzyme Drosha and its cofactor DGCR8. Here we show that the 5'-->3' exonuclease Xrn2 associates with independently transcribed miRNAs and, in combination with Drosha processing, attenuates transcription in downstream regions. We suggest that, after Drosha cleavage, a torpedo-like mechanism acts on nascent long precursor miRNAs, whereby Xrn2 exonuclease degrades the RNA polymerase II-associated transcripts inducing its release from the template. While involved in primary transcript termination, this attenuation effect does not restrict clustered miRNA expression, which, in the majority of cases, is separated by short spacers. We also show that transcripts originating from a miRNA promoter are retained on the chromatin template and are more efficiently processed than those produced from mRNA or snRNA Pol II-dependent promoters. These data imply that coupling between transcription and processing promotes efficient expression of independently transcribed miRNAs.

Citing Articles

MicroRNA biogenesis is broadly disrupted by inhibition of the splicing factor SF3B1.

Downie Ruiz Velasco A, Parsons A, Heatley M, Martin A, Smart A, Shah N Nucleic Acids Res. 2024; 52(15):9210-9229.

PMID: 38884273 PMC: 11347158. DOI: 10.1093/nar/gkae505.

The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma.

Chen J, He F, Peng H, Guo J Front Mol Biosci. 2024; 11:1378386.

PMID: 38584703 PMC: 10995332. DOI: 10.3389/fmolb.2024.1378386.

Recent progress in miRNA biogenesis and decay.

Bofill-De Ros X, Vang Orom U RNA Biol. 2023; 21(1):1-8.

PMID: 38031325 PMC: 10761092. DOI: 10.1080/15476286.2023.2288741.

Parameters of clustered suboptimal miRNA biogenesis.

Shang R, Lai E Proc Natl Acad Sci U S A. 2023; 120(41):e2306727120.

PMID: 37788316 PMC: 10576077. DOI: 10.1073/pnas.2306727120.

microRNAs in action: biogenesis, function and regulation.

Shang R, Lee S, Senavirathne G, Lai E Nat Rev Genet. 2023; 24(12):816-833.

PMID: 37380761 PMC: 11087887. DOI: 10.1038/s41576-023-00611-y.

References

Roush S, Slack F . The let-7 family of microRNAs. Trends Cell Biol. 2008; 18(10):505-16. DOI: 10.1016/j.tcb.2008.07.007. View

Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis M, Nervi C . A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005; 123(5):819-31. DOI: 10.1016/j.cell.2005.09.023. View

Guil S, Caceres J . The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol. 2007; 14(7):591-6. DOI: 10.1038/nsmb1250. View

Aguilera A . Cotranscriptional mRNP assembly: from the DNA to the nuclear pore. Curr Opin Cell Biol. 2005; 17(3):242-50. DOI: 10.1016/j.ceb.2005.03.001. View

Maniatis T, Reed R . An extensive network of coupling among gene expression machines. Nature. 2002; 416(6880):499-506. DOI: 10.1038/416499a. View

Yekta S, Shih I, Bartel D . MicroRNA-directed cleavage of HOXB8 mRNA. Science. 2004; 304(5670):594-6. DOI: 10.1126/science.1097434. View

Pawlicki J, Steitz J . Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production. J Cell Biol. 2008; 182(1):61-76. PMC: 2447899. DOI: 10.1083/jcb.200803111. View

Morlando M, Ballarino M, Greco P, Caffarelli E, Dichtl B, Bozzoni I . Coupling between snoRNP assembly and 3' processing controls box C/D snoRNA biosynthesis in yeast. EMBO J. 2004; 23(12):2392-401. PMC: 423293. DOI: 10.1038/sj.emboj.7600254. View

West S, Proudfoot N, Dye M . Molecular dissection of mammalian RNA polymerase II transcriptional termination. Mol Cell. 2008; 29(5):600-10. PMC: 2288634. DOI: 10.1016/j.molcel.2007.12.019. View

10.

Davis B, Hilyard A, Lagna G, Hata A . SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008; 454(7200):56-61. PMC: 2653422. DOI: 10.1038/nature07086. View

11.

Custodio N, Carmo-Fonseca M, Geraghty F, Pereira H, Grosveld F, Antoniou M . Inefficient processing impairs release of RNA from the site of transcription. EMBO J. 1999; 18(10):2855-66. PMC: 1171366. DOI: 10.1093/emboj/18.10.2855. View

12.

Connelly S, Manley J . A functional mRNA polyadenylation signal is required for transcription termination by RNA polymerase II. Genes Dev. 1988; 2(4):440-52. DOI: 10.1101/gad.2.4.440. View

13.

Chakrabarti S, James J, Mirmira R . Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, Pdx1. Importance of chromatin structure in directing promoter binding. J Biol Chem. 2002; 277(15):13286-93. DOI: 10.1074/jbc.M111857200. View

14.

Morlando M, Ballarino M, Gromak N, Pagano F, Bozzoni I, Proudfoot N . Primary microRNA transcripts are processed co-transcriptionally. Nat Struct Mol Biol. 2009; 15(9):902-9. PMC: 6952270. DOI: 10.1038/nsmb.1475. View

15.

Bentley D . The mRNA assembly line: transcription and processing machines in the same factory. Curr Opin Cell Biol. 2002; 14(3):336-42. DOI: 10.1016/s0955-0674(02)00333-2. View

16.

Gromak N, West S, Proudfoot N . Pause sites promote transcriptional termination of mammalian RNA polymerase II. Mol Cell Biol. 2006; 26(10):3986-96. PMC: 1488997. DOI: 10.1128/MCB.26.10.3986-3996.2006. View

17.

Megraw M, Sethupathy P, Corda B, Hatzigeorgiou A . miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res. 2006; 35(Database issue):D149-55. PMC: 1669779. DOI: 10.1093/nar/gkl904. View

18.

Kim Y, Kim V . Processing of intronic microRNAs. EMBO J. 2007; 26(3):775-83. PMC: 1794378. DOI: 10.1038/sj.emboj.7601512. View

19.

West S, Gromak N, Proudfoot N . Human 5' --> 3' exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature. 2004; 432(7016):522-5. DOI: 10.1038/nature03035. View

20.

Pawlicki J, Steitz J . Subnuclear compartmentalization of transiently expressed polyadenylated pri-microRNAs: processing at transcription sites or accumulation in SC35 foci. Cell Cycle. 2009; 8(3):345-56. PMC: 3004524. DOI: 10.4161/cc.8.3.7494. View