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cGAS detection of micronuclei links DNA damage and inflammatory mechanisms

Findings may shed light on inflammatory disease and body’s response to cancer: July 2017

Edinburgh study sheds light on how body may detect early signs of cancer

Andrew Jackson and colleagues at the MRC Human Genetics Unit, University of Edinburgh, have identified a new mechanism for how damage to the cell’s genetic material can trigger inflammation, setting in motion processes to remove damaged cells and keep tissues healthy.

A key molecule called cGAS is known to bind DNA, triggering inflammation. However, until now, it was not clear how this happens as DNA is usually physically separated from the rest of the cell inside the nucleus.

When damage occurs, fragments of DNA can get separated from the nucleus and form structures called micronuclei. Researchers at the MRC Human Genetics Unit at the University of Edinburgh discovered that cGAS can penetrate these micronuclei and bind to DNA, initiating mechanisms that lead to inflammation.

As DNA damage is often one of the early steps in the development of cancer, the detection of micronuclei by cGAS could therefore be an important early alarm system allowing the human body to detect and remove potentially cancerous cells before tumours form. This mechanism could also underlie inflammation occurring in certain types of autoinflammatory diseases.

 Our findings provide a possible new mechanism for how the body protects itself against cancer, but in some circumstances could instead trigger inflammatory disease. We hope that this research will inform future studies into the development of improved therapeutic approaches.

Dr Karen MackenzieMRC Human Genetics Unit, University of Edinburgh

The study, published in Nature, was funded by the Medical Research Council and Newlife - The Charity for Disabled Children.

Reference:

cGAS surveillance of micronuclei links genome instability to innate immunity

Karen J. Mackenzie, Paula Carroll, Carol-Anne Martin, Olga Murina, Adeline Fluteau, Daniel J. Simpson, Nelly Olova, Hannah Sutcliffe, Jacqueline K. Rainger, Andrea Leitch, Ruby T. Osborn, Ann P. Wheeler, Marcin Nowotny, Nick Gilbert, Tamir Chandra, Martin A. M. Reijns & Andrew P. Jackson

Nature, Advance Online Publication

http://dx.doi.org/10.1038/nature23449