DNA mutation with green wrench twisting a red nut
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TranslScientists often cite DNA damage as the cause for disease and medical issues, but a group of researchers from the UK have discovered a new mechanism of DNA repair that is linked to aging, cancer, and motor neuron disease (MND).

This new ‘toolkit’ for repairing damaged DNA is thought to be involved with several diseases as well as aging, and is involved in repairing DNA breakage. It was discovered by scientists at the Universities of Sheffield and Oxford, who hope to use this mechanism to protect patients from aging, cancer and neurological disease.

Professor Sherif El-Khamisy, co-founder and deputy director of the Healthy Lifespan Institute at the University of Sheffield and a professor from the Department of Molecular Biology and Biotechnology and the Neuroscience Institute at the University of Sheffield, who co-led the research said: “Failure to fix DNA breaks in our genome can impact our ability to enjoy a healthy life at an old age, as well as leave us vulnerable to neurological diseases like Motor Neuron Disease (MND).”

“We hope that by understanding how our cells fix DNA breaks, we can help meet some of these challenges, as well as explore new ways of treating cancer in the future.”

Until now, ways of repairing DNA damage caused by breakage have been poorly understood, but scientists hope to exploit this novel repair toolkit of proteins repair DNA breaks that occur during various cellular events that cause stress to the DNA molecules.

Published in Nature Communications, the research shows that a protein called TEX264, in combination with other enzymes, is able to recognize and ‘eat’ toxic proteins that stick to DNA and cause it to become damaged. This inappropriate association puts stress on the DNA molecule and causing shearing, leading to double stranded breaks in the genetic code. When this mechanism of protein removal is not working properly, an accumulation of broken, damaged DNA can occur, leading to cellular aging, cancer and neurological diseases such as MND. Unusable DNA in the cell can lead to many problems, both preventing the cell from working properly, as well as an accumulation of material that can interfere with the rest of the genetic code.

These findings could also have major implications for chemotherapy, which deliberately causes breaks in DNA when trying to kill cancerous cells. Scientists believe targeting the TEX264 protein may offer a new way to treat cancer.

Professor Kristijan Ramadan from the University of Oxford, who co-led the research, said: “Our finding of TEX264, a protein that forms the specialized machinery to digest toxic proteins from our DNA, significantly changes the current understanding of how cells repair the genome and so protect us from accelerated aging, cancer, and neurodegeneration. I believe this discovery has a great potential for cancer therapy in the future and we are already pursuing our research in this direction.”

Professor Ramadan added: “I am very proud of my research team who initially discovered the involvement of TEX264 in DNA repair.”

Oxford’s research was supported by several funding bodies, including the Medical Research Council. Backing was also received from the Oxford Institute for Radiation Oncology and Department of Oncology.

Professor El-Khamisy’s lab is funded by the Wellcome Trust and the Lister Institute of Preventive Medicine.

The work forms part of the research taking place at the University of Sheffield’s Healthy Lifespan Institute and the Neuroscience Institute.

The Healthy Lifespan Institute brings together 120 world-class researchers from a wide range of disciplines with the aim of slowing down the aging process and tackling the global epidemic of multi-morbidity—the presence of two or more chronic conditions—in a bid to help everyone live healthier, independent lives for longer and reduce the cost of care.

The Neuroscience Institute aims to translate scientific discoveries from the lab into pioneering treatments that will benefit patients living with neurodegenerative disorders.

Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields.

Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, GlaxoSmithKline, Siemens, and Airbus, as well as many UK and overseas government agencies and charitable foundations.

The next step of research in this field will be to test if the behavior and properties of protein TEX264 is altered in aging and neurological disorders such as MND. This can be assessed by studying samples of tissues from people who suffer from these conditions. Further study is certainly needed in this field, but if this initial study can be built upon, many diseases involved with damaged DNA could be impacted, and the way doctors view treating damaged DNA could be completely changed.

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