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 translational repression, deadenylation, decapping and subsequent target degradation. We have identified several key players in this process, including the GW182 proteins. Recently we have functionally dissected GW182 and shown that GW182 proteins directly recruit deadenylase complexes to promote rapid deadenylation of miRNA targets. 

  • elisa-izaurralde fig01
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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.

  • Izaurralde figure2
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Mechanism of miRNA-mediated gene silencing. miRNAs induce mRNA deadenylation, translational repression and decapping. Our group has shown that these processes are interlinked through interactions of the deadenylase complex (CCR4-NOT) with a repressor of translation and decapping activator (DDX6), which in turn interacts with the decapping complex (DCP2, DCP1, EDC4 and EDC3). We also showed how the CCR4-NOT and the PAN2-PAN3 deadenylase complexes are recruited to miRNA targets through the interaction of tryptophan (W)-containing motifs in GW182 proteins, which insert into hydrophobic pockets in NOT9 and PAN3.

Available PhD Projects

Project 1: Mechanisms of miRNA-mediated gene silencing.

Project 2: Role of mRNA deadenylase complexes in mRNA translational repression and degradation.

Selected Reading

1) Chen Y, Boland A, Kuzuoğlu-Öztürk D, Bawankar P, Loh B, Chang C-T, Weichenrieder O, Izaurralde, E (2014). A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing. Mol Cell 54:737–750.

2) Christie M, Boland A, Huntzinger E, Weichenrieder O, Izaurralde E (2013). Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Mol Cell 51:360–373.

3) Jonas S, Christie M, Peter D, Bhandari D, Loh B, Huntzinger E, Weichenrieder O, Izaurralde E (2014). An asymmetric PAN3 dimer recruits a single PAN2 exonuclease to mediate mRNA deadenylation and decay. Nat Struct Mol Biol 21:599-608.