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Post-transcriptional gene regulation

Elisa Izaurralde

Elisa Izaurralde

  • PhD in Molecular Biology, University of Geneva, 1985-89
  • Postdoctoral training, EMBL, Heidelberg, 1990-96
  • Group leader, University of Geneva and EMBL, 1996-2005
  • Director at the MPI for Developmental Biology since 2005

Research Interest

In eukaryotes, hundreds of proteins and small non-coding RNAs participate in post-transcriptional processes and their regulation. A subset of these factors co-localize in discrete cytoplasmic foci known as mRNA processing bodies or P-bodies (Fig. 1), suggesting that different post-transcriptional processes are interlinked. We see post-transcriptional processes as a complex network of regulatory circuits that together determine the expression levels of many genes.

Our research focuses on various post-transcriptional mechanisms: nonsense-mediated mRNA decay (NMD), mRNA translational repression and degradation, and miRNA-mediated gene silencing. Degradation of eukaryotic mRNAs is initiated by the removal of the poly(A) tail by deadenylases. Deadenylated mRNAs are then degraded from either the 5’- or the 3′-end by exonucleases. We are characterizing the protein complexes involved in mRNA degradation both at the functional and structural levels.  For miRNA-mediated gene silencing, we have shown that silencing is achieved through at least two distinct mechanisms: by repressing translation and by promoting mRNA decay. We have identified several key players in this process, including the GW182 proteins. Recently we have functionally dissected GW182, identified interacting partners and shown how GW182 proteins provide a binding platform for deadenylation factors to promote rapid deadenylation of miRNA targets.

Selected Reading

1) Kashima I, Jonas S, Jayachandran U, Buchwald G, Conti E, Lupas AN, Izaurralde E. (2010) SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay. Genes & Dev 24, 2440–50.

2) Igreja C, Izaurralde E. (2011) CUP promotes deadenylation and inhibits decapping of mRNA targets. Genes & Dev 25, 1955–67.

3) Braun JE, Huntzinger E, Fauser M, Izaurralde E. (2011) GW182 Proteins Directly Recruit Cytoplasmic Deadenylase Complexes to miRNA Targets. Mol Cell 44, 120–33.
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mRNA processing bodies (P-bodies in human cells). P-bodies are cytoplasmic domains where proteins involved in mRNA decay, silencing and translational repression accumulate.
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Mechanism of miRNA-mediated gene silencing. Silencing is effected by an Argonaute protein and GW182. GW182 binds the Argonaute protein through an N-terminal domain (N-term). GW182 promotes translational repression and mRNA degradation through the interaction of the C-terminal silencing domain (SD) with the poly(A)-binding protein (PABPC1) and with the two major cytoplasmic deadenylase complexes: the PAN2-PAN3 and the CCR4-NOT complex. The SD promotes rapid deadenylation of miRNA targets, which in turn reduces translation efficiency and facilitates target mRNA degradation by decapping and 5‘-to-3‘ exonucleolytic decay. The silencing domain consists of a PABP-binding motif 2 (PAM2), the Mid regions (M1 and M2) and the C-terminal region (C). The subunits of the deadenylation complexes are indicated.