DNA damage and disease

  • 20 April 2022
  • 2 minutes

Gonville & Caius College postgraduate student Liana Hardy (Biochemistry 2019) is funded by CRUK Cambridge Centre and working in Dr Svetlana Khoronenkova’s laboratory in the Department of Biochemistry, focusing on understanding of the links between deficiencies in the DNA damage response and the molecular nature of disease. The group, which includes PhD students Wen Cheng (St Edmund’s College) and Emily Talbot (Clare College), recently had a paper published and have summarised it for the Caius website.

Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunctionhttps://academic.oup.com/nar/article/50/5/2700/6536895

DNA, carrier of our genetic information, is chemically unstable and undergoes tens of thousands of damage events daily. Such DNA damage must be repaired to prevent disease including neurodegeneration, cancer and ageing. Our lab focuses on investigating the mechanisms by which defective signalling and repair of DNA damage drives disease, and whether these pathways could be  targeted therapeutically.  

Ataxia-telangiectasia (A-T) is a genetic disorder caused by loss-of-function in the ATM protein. ATM signals the presence of DNA damage, promoting its repair. ATM loss affects multiple systems in the body, but the most devastating symptom of A-T is degeneration of the brain. Individuals with A-T experience movement and coordination difficulties and rely on a wheelchair from childhood. However, how and why brain cells die in A-T is currently unknown. 

We recently discovered that ATM loss promotes hyperactivation, and dysfunctional behavior of microglia, immune cells of the brain that defend it against infections. DNA damage in A-T microglia drives an immune response in the absence of infection – so called sterile inflammation. These hyperactivated microglia inappropriately "eat” neurons and damage neuronal networks, contributing to neurodegeneration. We have uncovered molecular mechanisms that underpin microglial dysfunction in A-T and hope this will help to discover novel treatments in the future. 

Pictured: Liana Hardy fourth from left, with Dr Svetlana Khoronenkova pictured right.

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