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Department of Biochemistry

Dee Scadden

Investigating the fate of hyper-edited dsRNA.

We are interested in understanding the function of hyper-edited inosine-containing dsRNA (IU-dsRNA) in mammalian cells.

Adenosine deaminases that act on RNA (ADARs) constitute a family of enzymes that edit dsRNA in mammalian cells, whereby adenosine (A) residues are converted to inosine (I). Analyzing ADAR-deletion mutants has highlighted the importance of ADARs for normal cellular function. In particular, deletion of ADAR1 in mice results in embryonic lethality. However, the specific role of ADAR1 that underlies this observation is poorly understood.

While editing by ADARs can be selective, hyper-editing results in up to 50% of adenosine residues being converted to inosine. As ribosomes recognize inosine as guanosine, A-to-I editing has the potential to ‘recode’ RNAs, which results in incorporation of amino acids that are not directly encoded by the genome. In addition, hyper-edited dsRNAs (inosine-containing dsRNA; IU-dsRNA) are likely to contain localized changes within the RNA structure, as IU pairs are weaker than canonical Watson-Crick base pairs. Editing thus effectively gives rise to distinct molecules that will be readily recognizable in mammalian cells. Recent bioinformatic analyses have shown that the majority of editing events in mammalian cells occur within non-coding regions of RNAs, such as inverted Alu repeat sequences. However, while countless RNAs may be extensively edited, the function of IU-dsRNA in cells is unclear. Moreover, various studies have suggested diverse fates for IU-dsRNA.

We are interested in understanding the role of IU-dsRNA in mammalian cells. We have thus demonstrated that IU-dsRNA undergoes specific cleavage in various cell lysates, which suggests that hyper-editing can tag dsRNA for subsequent destruction6. Furthermore, our data has shown that Tudor-staphylococcal nuclease (TSN) binds specifically to IU-dsRNA and promotes its cleavage5. In addition to these findings, we have demonstrated that IU-dsRNA downregulates both endogenous and reporter gene expression in trans4. Importantly, we have shown that IU-dsRNA is sufficient to suppress interferon induction and apoptosis in mammalian cells3. This observation contributes to understanding the role of ADAR1p150 in mammalian cells that makes it essential for viability.

We have additionally shown that IU-dsRNA interacts specifically with various components of cytoplasmic stress granules4. Moreover, our data has confirmed that both TSN and ADAR1p150 are novel stress granule components2. While the role of ADAR1p150 in stress granules is not yet understood, we have recently shown that the Z-RNA binding domain found in ADAR1p150 is responsible for its localization to stress granules1.  Moreover, this is dependent on Z-RNA binding. Again, these findings support the idea that ADAR1p150 plays an important role in stress responses in mammalian cells. Our current research aims to elucidate mechanisms underlying these observations.


Key publications:

  1. Ng, S.K., Weissbach, R., Ronson, G. and Scadden, A.D.J. (2013).  Proteins that contain a functional Z-DNA binding domain localize to cytoplasmic stress granules.  Nucleic Acids Research, first published online August 27, 2013 doi:10.1093/nar/gkt750
  2. Weissbach, R. and Scadden, A.D.J. (2012).  Tudor-SN and ADAR1 are components of cytoplasmic stress granules.  RNA, 18, 462–471
  3. Vitali, P. and Scadden, A.D.J. (2010). Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis.  Nature Structural & Molecular Biology, 17, 1043–1050.
  4. Scadden, A.D.J. (2007).  Inosine-containing dsRNA binds a stress-granule-like complex and downregulates gene expression in trans. Molecular Cell, 28, 491–500.
  5. Scadden, A.D.J. (2005). The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nature Structural & Molecular Biology, 12, 489–496.
  6. Scadden, A.D.J. and Smith, C.W.J. (2001).  Specific cleavage of hyper-edited dsRNAs.  EMBO Journal, 20, 4243–4252.