Cancer research published in Science Advances

Posted date: 24 Aug 2020

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.

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