The £3.5M seven year project will give us a new understanding of how DNA in our genomes is packaged and will give new insights into how alterations in DNA structure cause human diseases.
In every mammalian cell DNA is wrapped around proteins to help protect it from damage and to regulate how it is “read” by the cell machinery. However the main protein for reading the DNA sequence is also a motor that can twist it. Like a rubber-band, if DNA becomes over or under-twisted it becomes distorted. To counteract this problem the cell has other machinery that can “cut” and reseal the DNA, releasing helical twist.
In normal cells there is a balance between the motors that introduce twist into the DNA and molecular scissors that release it. This project will use techniques we have recently developed with the chemistry department to examine patterns of DNA twisting across the human genome in different cell types and understand how altering the DNA twist affects the “reading” and “copying” of our DNA sequence. This is really critical for cells because untwisted DNA is much easier to “read” which in turn affects how cells make proteins.
In contrast, DNA that is very twisted is extremely difficult to “copy”, which triggers an effect making the genome very fragile. This often seen in human diseases including cancer but the reasons for this are complex and not understood. This project will examine these mechanisms to help us understand the earliest steps in the causes of some common diseases.
In addition to common diseases there are some very rare human genetic disorders, including Werner and Bloom Syndrome, where patients have a high frequency of cancer and premature aging. These disorders are caused by mutations in some of the motors that twist the DNA. This project will also help us to better understand these very rare diseases and in turn by studying cells from these patients will enable us to understand how alterations in DNA twisting cause the genome to become fragile.
Professor Nick Hastie, Director of the MRC Institute of Genetics and Molecular Medicine, said “This is a fantastic achievement and will enable Nick Gilbert and his team to carry out innovative research to create the discoveries of tomorrow. The MRC Institute of Genetics and Molecular Medicine is an excellent environment: we have great interactions between scientists studying biological mechanisms right through to clinicians working with patients to better understand their diseases.”
Dr Nick Gilbert said, “This fellowship is a fantastic opportunity for me and my team and I am please I can continue to address some of these most fundamental questions about DNA structure and better understand human diseases”