Deciphering novel transcriptional roles for Argonaute proteins in <em>Drosophila</em> development — ASN Events

Deciphering novel transcriptional roles for Argonaute proteins in Drosophila development (#172)

Linna Guo 1 2 , Olga Zaytseva 1 2 , Naomi C Mitchell 1 2 , Linda Parsons 3 , Gretchen Poortinga 4 , Ross D Hannan 1 4 , David L Levens 5 , Leonie M Quinn 1 2
  1. The John Curtin School of Medical Research, Australian National University , canberra
  2. The University of Melbourne, Melbourne, Victoria, AUSTRALIA
  3. Monash University, Melbourne, AUSTRALIA
  4. Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA
  5. National Cancer Institute, NIH, Bethesda, USA

The Argonaute (AGO) proteins have been extensively studied for their central roles in post-transcriptional gene regulation via their function in orchestrating siRNA-induced gene silencing. In Drosophila, there are two major members of the AGO family (AGO1 and 2). AGO1 has been shown to bind microRNAs (miRNAs) to form miRNA-induced silencing complexes (miRISCs), which target specific mRNAs to drive translational inhibition and/or transcript destabilization. AGO2 interacts with small interfering RNAs (siRNAs) to form RNA-induced silencing complexes (RISCs), to cleave mRNA target transcripts. Our studies suggest a new role for AGO1 as a direct transcriptional repressor. Co-IP-mass spectrometry studies positioned AGO1 in an interactome predominantly comprised of RNA Polymerase II transcriptional machinery. Intriguingly, this complex also includes the KH domain single-stranded RNA/DNA binding protein, Psi. Although previous literature has predominantly implicated Psi in RNA processing, our recent work has demonstrated key roles for Psi in RNA Pol II transcription(Guo et al., 2016).  In particular, Psi depletion impairs cell and tissue growth in a manner dependent on its capacity to activate transcription of the transcription factor, growth regulator and oncogene MYC. Our recent data demonstrates that co-knockdown of AGO1 rescues impaired cell and tissue growth associated with Psi depletion. Moreover, ChIP revealed enrichment for AGO1 across the MYC promoter and a significant increase in MYC mRNA abundance following AGO1 knockdown. Taken together, our data suggests AGO1 interacts with Psi and plays a role in repressing MYC transcription, cell and tissue growth. As MYC dysregulation is associated with 70% of all cancers, and the human ortholog of Psi (FUBP1) has also been implicated in MYC-driven tumours, this work will likely have implications for cancer initiation and progression.

  1. Guo, L., Zaytseva, et al. (2016). Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the mediator complex to modulate MYC transcription and tissue growth. Nucleic Acids Research.
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