Monday, 20 January 2020
Experts from the University of Nottingham have discovered a new DNA damage pathway, which could be a new lead in cancer research.
When cells lose control of how they multiply, they can cause cancer. They multiply by copying their DNA and DNA damage during copying is a well know target for cancer drugs.
In a recent study published in Nature Genetics, researchers have now found that DNA can also form hybrids with a chemically modified form of its cousin, RNA.
The researchers, from the School of Medicine at the University, found that chemically modified RNA, known as m6A RNA can bind to DNA and stop cell division and increase DNA damage.
DNA encodes the genetic information in all living organisms by copying (transcription) this information to RNA, some of which encode proteins. Often this transcription process is not complete, so the RNA does not leave the DNA and forms a structure called RNA: DNA hybrid. The formation of RNA: DNA hybrids leaves a part of the DNA vulnerable to attack, resulting in mutations, a feature of many diseases, including cancer and neurodegeneration.
In this study, The Ruzov lab and several of his collaborators uncovered the presence of a chemical modification (N6-methyladenosine; m6A) on the RNA component of RNA: DNA hybrids. Although RNA: DNA hybrids are known for decades, this study is the first to show that a non-canonical nucleic acid base is present on the RNA component of the hybrids.
Abdulkadir Abakir who is a Medical Research Council-funded PhD candidate and a lead author of the study said: ”As soon as we detected m6A on the RNA component of the hybrids, we had the result independently validated by several of our collaborators, and we became super excited as it can be a novel target in cancer therapy.”
By combining the purification of these structures with next-generation sequencing techniques, the experts developed a novel technique to more precisely map regions of our genome marked with m6A modified RNA: DNA hybrids. The authors show that most of the RNA: DNA hybrids in human cells are marked by m6A and their accumulation varied depending on the cell cycle stage.
Dr Alexey Ruzov, Assciate Professor in Stem Cell Biology at the University and the senior author of the study, said: “After confirming the presence of m6A on the hybrids, we became very excited to know the biological function of m6A on the RNA: DNA hybrids”.
The authors teased apart which proteins can directly bind m6A modified hybrids and found a protein, YTHDF2, which is known to target m6A single stranded mRNA also directly binds m6A modified DNA-RNA hybrids both in vitro and in vivo. When they blocked YTHDF2 in human cells and mouse tissues, they increased m6A modified RNA: DNA hybrids and stopped cell growth and markedly increased DNA damage.
We expect the findings to have far reaching implications in our basic understanding of cancer biology as genomic instability underlies almost all types of cancer. The findings open up a new avenue for new DNA damage therapies, a rapidly growing area of new cancer drug development”.
Story credits
A full copy of the study can be found here, or contact the Ruzov lab on e-mail: alexey.ruzov@nottingham.ac.uk
Notes to editors:
About the University of Nottingham
Ranked 32 in Europe and 16th in the UK by the QS World University Rankings: Europe 2024, the University of Nottingham is a founding member of the Russell Group of research-intensive universities. Studying at the University of Nottingham is a life-changing experience, and we pride ourselves on unlocking the potential of our students. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement.
Nottingham was crowned Sports University of the Year by The Times and Sunday Times Good University Guide 2024 – the third time it has been given the honour since 2018 – and by the Daily Mail University Guide 2024.
The university is among the best universities in the UK for the strength of our research, positioned seventh for research power in the UK according to REF 2021. The birthplace of discoveries such as MRI and ibuprofen, our innovations transform lives and tackle global problems such as sustainable food supplies, ending modern slavery, developing greener transport, and reducing reliance on fossil fuels.
The university is a major employer and industry partner - locally and globally - and our graduates are the second most targeted by the UK's top employers, according to The Graduate Market in 2022 report by High Fliers Research.
We lead the Universities for Nottingham initiative, in partnership with Nottingham Trent University, a pioneering collaboration between the city’s two world-class institutions to improve levels of prosperity, opportunity, sustainability, health and wellbeing for residents in the city and region we are proud to call home.
More news…