Breaking the A chain: regulating mRNAs in development through CCR4 deadenylase

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Abstract

Post-transcriptional mechanisms of gene regulation have long been implicated in specifying embryonic pattern in many organisms. Experiments in Caenorhabditis elegans, Drosophila, and Xenopus have recently converged, pointing to the CCR4 deadenylase complex as a key effector that modulates the expression of proteins from specific germline mRNAs.

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SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase.

Howard D Lipshitz, Nicholas Westwood, Tomas Babak … (2006)

In animals, egg activation triggers a cascade of posttranscriptional events that act on maternally synthesized RNAs. We show that, in Drosophila, the PAN GU (PNG) kinase sits near the top of this cascade, triggering translation of SMAUG (SMG), a multifunctional posttranscriptional regulator conserved from yeast to humans. Although PNG is required for cytoplasmic polyadenylation of smg mRNA, it regulates translation via mechanisms that are independent of its effects on the poly(A) tail. Analyses of mutants suggest that PNG relieves translational repression by PUMILIO (PUM) and one or more additional factors, which act in parallel through the smg mRNA's 3' untranslated region (UTR). Microarray-based gene expression profiling shows that SMG is a major regulator of maternal transcript destabilization. SMG-dependent mRNAs are enriched for gene ontology annotations for function in the cell cycle, suggesting a possible causal relationship between failure to eliminate these transcripts and the cell cycle defects in smg mutants.

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PUF proteins bind Pop2p to regulate messenger RNAs.

E B Hook, David Goldstrohm, Montrell Seay … (2006)

PUF proteins, a family of RNA-binding proteins, interact with the 3' untranslated regions (UTRs) of specific mRNAs to control their translation and stability. PUF protein action is commonly correlated with removal of the poly(A) tail of target mRNAs. Here, we focus on how PUF proteins enhance deadenylation and mRNA decay. We show that a yeast PUF protein physically binds Pop2p, which is a component of the Ccr4p-Pop2p-Not deadenylase complex, and that Pop2p is required for PUF repression activity. By binding Pop2p, the PUF protein simultaneously recruits the Ccr4p deadenylase and two other enzymes involved in mRNA regulation, Dcp1p and Dhh1p. We reconstitute regulated deadenylation in vitro and demonstrate that the PUF-Pop2p interaction is conserved in yeast, worms and humans. We suggest that the PUF-Pop2p interaction underlies regulated deadenylation, mRNA decay and repression by PUF proteins.

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Smaug recruits the CCR4/POP2/NOT deadenylase complex to trigger maternal transcript localization in the early Drosophila embryo.

Jennifer Semotok, Ramona Cooperstock, Benjamin Pinder … (2005)

Asymmetric localization of mRNAs within cells promotes precise spatio-temporal control of protein synthesis. Although cytoskeletal transport-based localization during Drosophila oogenesis is well characterized, little is known about the mechanisms that operate to localize maternal RNAs in the early embryo. One such mechanism-termed "degradation/protection"-acts on maternal Hsp83 transcripts, removing them from the bulk cytoplasm while protecting them in the posterior pole plasm. Here, we identify the RNA binding protein, Smaug, previously known as a translational repressor of nanos, as a key regulator of degradation/protection-based transcript localization. In smaug mutants, degradation of Hsp83 transcripts is not triggered, and, thus, localization does not occur. Hsp83 transcripts are in an mRNP complex containing Smaug, but Smaug does not translationally repress Hsp83 mRNA. Rather, Smaug physically interacts with the CCR4/POP2/NOT deadenylase, recruiting it to Hsp83 mRNA to trigger transcript deadenylation and degradation. When Smaug is targeted to heterologous stable reporter transcripts in vivo, these are deadenylated and destabilized. A deletion that removes the gene encoding CCR4 exhibits dose-sensitive interactions with Smaug in both a loss-of-function and a gain-of-function context. Reduction of CCR4 protein levels compromises Hsp83 transcript destabilization. Smaug triggers destabilization and localization of specific maternal transcripts through recruitment of the CCR4/POP2/NOT deadenylase. In contrast, Smaug-mediated translational repression is accomplished via an indirect interaction between Smaug and eIF4E, a component of the basic translation machinery. Thus, Smaug is a multifunctional posttranscriptional regulator that employs distinct mechanisms to repress translation and to induce degradation of target transcripts.

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: http://www.f1000biology.com/about/biography/1980258494269782

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Journal ID (nlm-ta): F1000 Biol Rep

Title: F1000 Biology Reports

Publisher: Biology Reports Ltd

ISSN (Electronic): 1757-594X

Publication date (Electronic): 17 March 2009

Publication date Collection: 2009

Volume: 1

Electronic Location Identifier: 20

Affiliations

[1]simpleDepartment of Biology and Developmental Biology Research Initiative, McGill University 1205 Avenue Docteur Penfield, Montréal, QC H3A 1B1Canada

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Publisher ID: 20

DOI: 10.3410/B1-20

PMC ID: 2920682

PubMed ID: 20948665

SO-VID: d6ab1eae-3f39-4502-89e8-64b0edbf9229

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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You may not use this work for commercial purposes

Breaking the A chain: regulating mRNAs in development through CCR4 deadenylase

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Abstract

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Malaria vaccine development

Most cited references 16

SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase.

PUF proteins bind Pop2p to regulate messenger RNAs.

Smaug recruits the CCR4/POP2/NOT deadenylase complex to trigger maternal transcript localization in the early Drosophila embryo.

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