ERA Chair - RNA and Immunity - Mary O´Connell
ERA Chair - RNA and Immunity - Mary O´Connell

PhD Topics

1.  ADAR2 RNA editing in CNS

Supervisor: Liam Keegan, Ph.D.

Consultant: prof. Mary Anne O'Connell

The main part of the work will use Drosophila but the student will also have access to Adar2 mutant mice which model the severe epilepsy caused by ADAR2 mutations in humans. Adar2 mutant mouse pups develop seizures and die at or before weaning.
In Drosophila we found that Adar mutant phenotypes can be rescued by increased autophagy which clears synaptic defects. The new student will join Anzer Khan who is near the end of his PhD to continue studying the rescues of Adar mutant phenotypes by Hsc70-4 to understand how Adar mutant defects arise and are rescued by increased Hsc70-4.
The Adar mutant defects may be due to loss of RNA editing in specific transcripts such as synaptotagmin, synapsin and cacophony that encode key synaptic proteins. We will try to rescue Adar mutant defects by expressing edited forms of cDNAs for these specific transcripts that are available within the Drosophila community

Recommended literature
ADAR RNA editing in innate immune response phasing, in circadian clocks and in sleep. Sinigaglia K, Wiatrek D, Khan A, Michalik D, Sambrani N, Sedmík J, Vukić D, O'Connell MA, Keegan LP. Biochim Biophys Acta Gene Regul Mech. 2019 Mar;1862(3):356-369.  Review. PMID:30391332
ADAR RNA editing in human disease; more to it than meets the I. Gallo A, Vukic D, Michalík D, O'Connell MA, Keegan LP. Hum Genet. 2017 Sep;136(9):1265-1278. Review. PMID: 28913566
The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster. Li X, Overton IM, Baines RA, Keegan LP, O'Connell MA. Nucleic Acids Res. 2014 Jan;42(2):1139-51. doi: 10.1093/nar/gkt909. Epub 2013 Oct 16. PMID: 24137011
Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects. Keegan LP, McGurk L, Palavicini JP, Brindle J, Paro S, Li X, Rosenthal JJ, O'Connell MA. Nucleic Acids Res. 2011 Sep 1;39(16):7249-62. doi: 10.1093/nar/gkr423. Epub 2011 May 27. PMID: 21622951
Tuning of RNA editing by ADAR is required in Drosophila. Keegan LP, Brindle J, Gallo A, Leroy A, Reenan RA, O'Connell MA. EMBO J. 2005 Jun 15;24(12):2183-93. Epub 2005 May 26. PMID: 15920480

RG: ERA Chair - Mary O'Connell Research Group

Keywords: RNA modification, ADAR, genetics


2. Investigating the regulation of the RNA modifying enzyme ADAR1 and how it regulates other biological pathways and diseases

Supervisor: prof. Mary Anne O'Connell

Consultant: Liam Keegan, Ph.D.

The ADAR enzymes convert adenosine into inosine in dsRNA. Inosine is one of the most abundant and best studied modifications found in different classes of RNA. Hundreds of millions of positions have been identified within the human transcriptome where inosine can occur. The fact that levels of inosine have been found to increase in the RNAs of many cancers has sparked huge interest in this field. The levels of inosine in RNA have also been shown to profoundly affect activation of innate immunity in cancer, infection, and autoimmune diseases.  The goal of this PhD project is to understand how ADAR1 is regulated and it in turn regulates different cellular processes. The methods used will include basis molecular biology techniques such as immune-blotting, RNA isolation, qPCR, cell culture etc. The candidate will have to be proficient in English, both spoken and written, be experienced in molecular biology or immunology.

Recommended literature:
M. A. O'Connell, N. M. Mannion, L. P. Keegan, The Epitranscriptome and Innate Immunity. PLoS Genet 11, e1005687 (2015).
A. Gallo, D. Vukic, D. Michalik, M. A. O'Connell, L. P. Keegan, ADAR RNA editing in human disease; more to it than meets the I. Hum Genet 136, 1265-1278 (2017).
N. M. Mannion et al., The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep 9, 1482-1494 (2014).
G. I. Rice et al., Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nature genetics 44, 1243-1248 (2012).

RG: ERA Chair - Mary O'Connell Research Group

Keywords: RNA modification, epitranscriptome, ADAR, innate immunity, cancer