Recipe for perfect balance of breaks and repairs in our genome could help fight cancer

Recipe for the perfect balance of breaks and repairs in our genome could help fight cancer and brain ageing

  • New discovery gives insight into chemotherapy resistant cancers such as rhabdosarcoma – the most common soft tissue cancer in children
  • Findings could have significant implications in brain ageing which has an effect on memory and cognitive function

Scientists at the University of Sheffield have discovered what keeps the perfect balance of breaks and repairs in our DNA – something which could help improve the success of chemotherapy and combat neurodegeneration associated with ageing.

Our genome, where precious genetic information is stored, is challenged with thousands of breaks every day.

Cells possess an army of proteins that search for, detect and fix these breaks to maintain genome integrity, but little is known about how the cell fine-tunes the level of response in these repair factories to suit each and every repair event.

The level of proteins in our cells is controlled by synthesis and degradation. Cells get rid of proteins when not needed by attaching a small peptide called ubiquitin.

The new study, led by Dr Sherif El-Khamisy at the University of Sheffield's Department of Molecular Biology and Biotechnology, has revealed an enzyme called UCHL3, which controls DNA repair by removing ubiquitin marks from TDP1 – a DNA repair protein. The findings also have implications in brain ageing which has an affect on memory, cognitive function and learning.

An overexpression of UCHL3 causes less ubiquitination of TDP1 and increases its protein level, which is found in chemotherapy resistant cancers such as rhabdosarcoma – the most common soft tissue sarcoma in children, which has a debilitating effect on the muscles, tendons and cartilage.

Too little UCHL3, however, was found to cause more ubiquitination of TDP1 reducing its level in neurological diseases such as ataxias – a group of disorders that affect co-ordination, balance and speech.

Dr El-Khamisy said: "This study identifies UCHL3 as a novel therapeutically druggable target where suppression of its activity can improve cancer treatment, whereas encouraging and fuelling its activity can combat neurodegeneration.

"Defective DNA repair is a common theme in a number of neurological disorders including motor neuron disease and dementia. Finding novel approaches to fuel the cell's ability to repair genomic breaks may hold promise in improving treatment of a broad range of neurological diseases."

The five-year study is funded by a Wellcome Trust Investigator Award to Dr El-Khamisy and involved collaborations across departments at The University of Sheffield and internationally.

The full study is published today (12 June 2018) in the journal Cell Reports.

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For further information please contact: Amy Huxtable, Media Relations Officer, University of Sheffield, 0114 222 9859

Notes to editors

The University of Sheffield

With almost 29,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world's leading universities.

A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines.

Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in.

Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work For 2018 and for the last eight years has been ranked in the top five UK universities for Student Satisfaction by Times Higher Education.

??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, Glaxo SmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations.

The Wellcome Trust

Wellcome exists to improve health for everyone by helping great ideas to thrive.

The Wellcome Trust is a global charitable foundation, both politically and financially independent. They support scientists and researchers, take on big problems, fuel imaginations, and spark debate.

For more information please visit: https://wellcome.ac.uk/home

The Lister Institute of Preventative Medicine

The Lister Institute of Preventive Medicine was founded in 1891 and is one of the UK's oldest medical charities.

Originally a Research Institute developing, and subsequently producing on a commercial scale, vaccines and antitoxins it has over the years adapted to the changing research environment; always seeking to support research in an innovative way. Take a look at our heritage and find out more about us.

Today, from its endowment funds, it is a grant-giving charity whose principal award is the Lister Research Prize Fellowship. The Institute has sought to retain the 'Lister family' tradition and remains in touch with all its former and current Fellows.

<p>For more information please visit: http://www.lister-institute.org.uk/  </p>                               <p><strong>Media Contact</strong></p>    <p>Amy Huxtable<br />[email protected]<br />01-142-229-859<br /> @sheffielduni     

http://www.shef.ac.uk

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