Karen Mackenzie, United Kingdom

The University of Edinburgh Institute of Genetics and Molecular Medicine
Dr Karen Mackenzie is a Clinical Lecturer in Genetics at the University of Edinburgh. She studied Medicine at the University of Edinburgh and graduated with Honours in 2004, additionally gaining an Intercalated BSc in Immunology.Following time working in clinical Paediatrics, Dr Mackenzie gained her PhD in 2011 working in the Labs of Professor Stephen Anderton and Professor Jürgen Schwarze, University of Edinburgh, focusing on T cell tolerance induced by peptide immunotherapy. As a post-doctoral scientist in the Lab of Professor Andrew Jackson, University of Edinburgh, she investigated immunological aspects of the genetic condition Aicardi-Goutières syndrome (AGS). During this time, she described the role of the cGAS-STING pathway in initiating immune responses in AGS caused by deficiencies in the genome stability enzyme, RNase H2. This led to the discovery that micronuclei are a source of self-DNA capable of triggering inflammatory responses – a mechanism which has wide ranging implications for anti-neoplastic responses and inflammation in the context of DNA damage. Dr Mackenzie is currently completing her training in Clinical Genetics and will focus her future research on determining novel mechanisms of immune tolerance using insights from genetic inflammatory conditions.

Presenter Of 1 Presentation

Plenary Session No Topic Needed


Lecture Time
14:30 - 15:00
20.09.2019, Friday
Session Time
14:30 - 16:00
Presentation Topic
No Topic Needed


Abstract Body

Aicardi-Goutières syndrome (AGS) is a rare genetic condition associated with brain inflammation in children and is associated with a Type 1 Interferon response. AGS can be viewed as a genetic mimic of congenital viral infection. Mutations in ribonuclease H2 (RNase H2) genes, which code for an enzyme that is vital for genome stability, are the most common cause of AGS. We have previously shown that immune activation in RNase H2 deficiency is associated with triggering of the DNA sensor cGAS and its adaptor protein STING. This raised the important question of how cGAS is activated in RNase H2 deficiency.

We observed cGAS localising to structures known as micronuclei within RNase H2 deficient cells. Micronuclei are formed during mis-segregation of DNA during mitosis, are associated with genome instability and are often a feature in tumour cells. cGAS localisation to micronuclei was not restricted to RNase H2 deficiency, also occurring following exogenous irradiation-induced DNA damage and in micronuclei arising spontaneously in human cancer cells. Breakdown of the micronuclear envelope resulted in rapid accumulation of cGAS, providing an explanation of how cytosolic cGAS gains access to this immunostimulatory DNA. Furthermore, live-cell laser microdissection and single cell transcriptomics showed that interferon-stimulated gene expression was preferentially induced in cells with micronuclei. These findings support a cell-intrinsic immune surveillance mechanism which could detect a range of neoplasia promoting processes, but where aberrant activation triggers autoinflammatory disease (Mackenzie KJ et al, Nature;548:461).