Unraveling the Mystery of DNA Attacks in Cells’ Powerhouse could Pave Way for New Cancer Treatments

Work led by Dr Sherif El-Khamisy, Director of the Center of Genomics at Zewail City & Chair of Molecular Medicine at the University of Sheffield, in collaboration with the University of Sussex, University of Newcastle and St Jude hospital in the US unravels the mystery of DNA attacks in cells’ powerhouse - the mitochondria -  providing novel avenues to tackle neurodegenerative diseases and cancer.

The research findings published on 28 April 2017 in Science Advances were selected for the front cover of the journal and attracted the attention of International Press including the BBC. The study entitled “Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical induced DNA damage” is timely since it highlights the importance of nuclear-mitochondrial interactions, which is important for the recently approved mitochondrial replacement therapies or otherwise known as Three Parent Babies. It unravels a novel genetic pathway to maintain mitochondrial genome stability. These findings have broad and important implications since maintaining mitochondrial DNA integrity is an important factor in many aspects of cell biology impacting on cancer, ageing and neurodegeneration.

The study reveals the enzyme TDP1 - which is already known to have a role in repairing damaged DNA in the cell’s nucleus - is also responsible for repairing damage to mitochondrial DNA (mtDNA). The study employed a multidisciplinary approaches ranging from forward genetics, biochemical purification and quantification of mitochondrial DNA breaks, mouse genetics, bioenergetics, spectroscopy and cellular DNA repair assays, which led to unraveling a novel mitochondrial DNA repair pathway and revealed its role in regulating mitochondrial gene transcription and oxygen consumption.

 The newly identified genetic pathway confers protection against oxidative stress induced damage and thus promotes cell function and viability. this discovery has implications on the recently licensed mitochondrial replacement therapies.

Lead author of the study, Professor Sherif El-Khamisy said: “Each mitochondria repair toolkit has unique components – enzymes - which can cut, hammer and seal the breaks. The presence of these enzymes is important for energy production. “Defects in repairing DNA breaks in the mitochondria affect vital organs that rely heavily on energy such as the brain. It also has implications on mitochondria replacement therapies recently approved in the UK and known as ‘three parent babies’.”

El-Khamisy adds: "If we can find a way to selectively damage the mitochondria in the cancer cells, by preventing or slowing its repair mechanism, this could be really promising."

In Egypt, pathological and drug-induced liver injuries are major health challenges. They often require partial liver transplantation, the success of which differs across individuals. This study provides evidence for the importance of assessing mitochondrial TDP1 and TOP1mt genetic variants and function to improve the success of tissue regeneration.


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