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Cancer research published in Science Advances

Cancer is a disease that has touched us all, and although we now know a lot about how cancers develop and grow, we still have a lot to learn.  A major factor in cancer development and in treatment resistance is the presence of genome instability. This essentially involves frequent alterations to the genomic DNA of the cell, including changes to the letters of the genetic code as well as more obvious changes such as chromosome deletions, or even movement of large DNA fragments from one chromosome to another. Work in UKRI Future Leader Fellow Dr Chris Staples’ laboratory housed at the North West Cancer Research Institute (in the School of Medical Sciences at Bangor University) focuses on how cells normally prevent such genome instability from occurring.

In many cancers, a phenomenon called replication stress is at the heart of these genome instability issues. All cells have to replicate their DNA to divide into two ‘daughter’ cells, and cancer cells are no exception – indeed, they divide more rapidly than normal cells. The term ‘replication stress’ is used to describe any scenario where the cells DNA replication machinery gets into difficulties, and when this occurs, DNA damage and genome instability can result.

When the DNA replication machinery gets stuck, the newly-formed DNA is vulnerable to attack by DNA-chewing enzymes called nucleases, particularly a nuclease called MRE11, which is normally involved in fixing broken DNA.

Research in the Staples laboratory led at the bench by Dr Laura Bennett identified a largely unstudied protein called MRNIP, as a novel ‘protector’ of this newly-formed DNA. Cancer cells in which the MRNIP gene is ‘knocked out’ by CRISPR-Cas9 technology exhibit high levels of DNA damage, caused partly by excessive degradation of newly-formed DNA by MRE11. The researchers found that MRNIP binds to MRE11 and functions to reduce the rate at which it digests DNA. Without MRNIP, MRE11 extensively degrades this newly-formed DNA, and DNA damage and chromosomal instability ensues.

Dr Staples said, ‘We are really proud of this work, which highlights the importance of controlling the activity of nuclease enzymes to normal cellular function. Our cells are full of these types of enzymes, and it is becoming clearer that they can only perform their beneficial functions – which are often essential for life - with the help of a network of regulators like MRNIP. Over the coming years, we will be investigating the role of MRNIP in a range of cancers, as well as attempting to identify the precise mechanism via which MRNIP regulates MRE11 function’.

The study was published in Science Advances.

Publication date: 26 July 2020