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Vol. 20, Issue 15, 3459-3470, August 1, 2009

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The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Viktoria Hessle^*, Petra Björk^*, Marcus Sokolowski^*,, Ernesto González de Valdivia^*, Rebecca Silverstein^*, Konstantin Artemenko, Anu Tyagi^*, Gianluca Maddalo, Leopold Ilag, Roger Helbig^*, Roman A. Zubarev, and Neus Visa^*

Departments of *Molecular Biology and Functional Genomics and Analytical Chemistry, Stockholm University, SE-10 691 Stockholm, Sweden; and Division of Molecular Biometry, Institute for Cell and Molecular Biology, Uppsala University, Uppsala, Sweden

Submitted January 26, 2009; Revised May 19, 2009; Accepted May 21, 2009
Monitoring Editor: Wendy Bickmore

Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

Present address: Department of Public Health Sciences, Karolinska Institutet, SE-17 177 Stockholm, Sweden.

Address correspondence to: Neus Visa (neus.visa{at}molbio.su.se)