Monday, 20 January 2020
Experts from the 糖心原创 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 , 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鈥�.
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A full copy of the study can be found or contact the Ruzov lab on e-mail: alexey.ruzov@nottingham.ac.uk
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