Oral Presentation 39th Annual Lorne Genome Conference 2018

Enhancing the spatiotemporal sub-nuclear sequestration of RNA binding proteins by manipulating paraspeckle size (#28)

Archa Fox 1 2 , Alina Naveed 2 3 , Jack Cooper 1 , Ruohan Li 1 , Steve Wilton 4 , Sue Fletcher 4 , Charlie Bond 2 , Tao Liu 5
  1. School of Human Sciences, University of Western Australia, Crawley, WA, Australia
  2. School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia
  3. School of Human Sciences and Molecular Sciences, University of WA, Perth, WA, Australia
  4. Centre for Comparative Genomics, Murdoch University, Perth, WA, Australia
  5. Children's Cancer Institute, Kensington , NSW, Australia

Proteostasis of many important RNA binding proteins is critical for a variety of diseases including neurodegeneration and cancer. Given that the overall levels of these proteins can remain relatively constant, cells have developed other ways of regulating their function, including by spatiotemporal control of protein location. Paraspeckles are sub-nuclear RNA-protein bodies that form in response to cellular stress. Paraspeckle formation is triggered by enhanced transcription of a 23kb long noncoding RNA, NEAT1 (Nuclear Paraspeckle Assembly Transcript 1) that acts as a scaffold for binding by many different nuclear RNA binding proteins. This network of proteins then recruits additional proteins and RNAs to form a micron-scale subnuclear body, the paraspeckle.

We and others have shown that one function of paraspeckles is to ‘sponge’ up RNA binding proteins, effecting spatiotemporal sequestration of these proteins and thereby having a flow-on effect on their downstream targets. Here I will present new results on an antisense-oligonucleotide based method to enhance paraspeckle formation as a means of manipulating the sub-nuclear localisation of RNA binding proteins.  We have specifically explored using this tool to manipulate paraspeckles in the context of the cancer neuroblastoma, as a means of sponging the oncogenic paraspeckle protein, NONO.