We are interested in how RNA editing by ADAR proteins changes the RNA landscape and contributes to normal physiology and cancer. We are studying the physiological roles of ADAR1 and the consequences of its editing of cellular RNAs. We are particularly interested in how A-to-I editing intersects with the cellular innate immune system – the cell’s defence against foreign RNA, such as virus – and how these pathways intersect. This is relevant to understanding how mutations in ADAR1 cause human disease, such as the rare childhood disease Aicardi-Goutières Syndrome.
We are also interested in understanding how rare human disease syndromes, particularly those related to cancer predisposition. In this area we are focused on Rothmund-Thomson Syndrome and how the gene identified in this disease, RECQL4, functions. We generate models to identify and develop new understanding of how the key genes identified in these syndromes function and to use to identify and test potential new therapeutic options for these diseases.
Current research projects
RNA editing by ADAR proteins
ADAR proteins catalyse the conversion of adenosine bases in RNA to inosine (termed A-to-I editing). We have used mouse genetics to define the role of ADAR1 in vivo, demonstrating that the editing of RNA by ADAR1 is essential to prevent activation of the innate immune sensing system by endogenous RNA. We are continuing to study the role of A-to-I editing in both normal physiology and disease.
We are particularly interested in understanding the cellular and organismal consequences of A-to-I editing, the protein/gene networks that the cell can use to regulate the response to un-edited cellular dsRNA and how these intersect with pathologies associated with changes in ADAR1 function or editing (cancer, infection, autoinflammatory conditions).Rare human syndromes and Osteosarcoma (bone cancer)
Osteosarcoma is the most common cancer of bone. We have developed and characterised a unique model of this cancer, based on our understanding of the genetics of human osteosarcoma. Our model closely mirrors the human cancer in terms of histology, transcriptional profile, cytogenetics and metastatic dissemination.
We are using these models of human osteosarcoma to further understand the genetics of this disease, as well as a pre-clinical model to explore new therapeutic approaches to treat both primary and metastatic disease. We are interested in how mutations in the genes that cause rare human cancer predisposition syndromes function and cause osteosarcoma.
We are currently focused on understanding the functions of RECQL4, a cause of the rare inherited Rothmund-Thomson Syndrome, where patients are highly predisposed to develop osteosarcoma.
- Ankita Goradia, Lab Manager and Senior Research Assistant
- Scott Taylor, Senior Research Assistant
- Zhen Liang, PhD Student
Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as non-self. Science 2015 Sep 4;349(6252):1115-20.
Heraud-Farlow JE, Chalk AM, Linder SE, Li Q, Taylor S, White JM, Pang L, Liddicoat BJ, Gupte A, Li JB, Walkley CR. Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biology (2017) Sep 5;18(1):166.
Smeets MF, Tan SY, Xu JJ, Anande G, Unnikrishnan A, Chalk AM, Taylor SR, Pimanda JE, Wall M, Purton LE, Walkley CR. Srsf2P95H initiates myeloid bias and myelodysplastic/myeloproliferative syndrome (MDS/MPN) from hemopoietic stem cells. Blood 2018 Aug 9;132(6):608-621.
Castillo-Tandazo W, Smeets M, Murphy V, Liu R, Hodson C, Heierhorst J, Deans AJ, Walkley CR. ATP-dependent helicase activity is dispensable for the physiological functions of Recql4. PLoS Genetics 2019 Jul 5;15(7):e1008266.
Chalk AC, Taylor S, Heraud-Farlow JE, Walkley CR. The majority of A-to-I RNA editing is not required for mammalian homeostasis. Genome Biology 2019 20:268.
Xu JJ, Chalk AM, Wall M, Langdon WY, Smeets MF, Walkley CR. Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice.
Leukemia. 2022 Oct 21. doi: 10.1038/s41375-022-01727-6
ORCID profile: https://orcid.org/0000-0002-4784-9031
Google Scholar profile: https://scholar.google.com/citations?user=w8UjFlcAAAAJ&hl=en&oi=ao