Genetic double-agents unmasked

Babraham Institute and Cancer Research UK scientists have discovered that certain enzymes with a key activity in the immune system may be important in stem-cell development, but may also work against us by contributing to the occurrence of cancer.

A family of enzymes known as DNA deaminases beneficially mutates the genetic code of antibodies to improve their ability to recognise foreign bodies. The usual target for the enzymes’ activity is cytosine (C), one of the four building blocks of DNA, however this research has shown that the enzymes can also target another DNA component: methylcytosine (cytosine carrying a methyl chemical group).

The discovery may help to explain how methylcytosine is removed from DNA in naturally-occurring situations, such as stem-cell development, but it also suggests a possible mechanism for the mutations that occur in up to one third of hereditary diseases and many cancers. Hence DNA deaminases may be acting as ‘double-agents’.

Dr Wolf Reik, Head of Developmental Genetics and Imprinting at the Babraham Institute, explains: “The removal of methyl groups from DNA is a sought-after activity implicated in the ability of stem-cells to develop into any other cell in the body, but it is uncertain how this demethylation could occur. The activity we have found in DNA deaminases provides a potential explanation of the mechanism. However, incorrect repair of the DNA during this process may result in mutations that could increase a person’s chance of developing cancer.”

Methylcytosine is an example of an ‘epigenetic’ mark – a heritable modification of DNA that affects the way in which a gene is read, without changing the DNA code itself. Epigenetics is an important area of research because epigenetic marks are essential for normal development and they can become misdirected in the cell, leading to cancer and other human diseases.

The discovery of the actions of these enzymes, described in a paper published in the Journal of Biological Chemistry, was made by Dr Hugh Morgan and colleagues, working with Dr Wolf Reik at the Babraham Institute, and in collaboration with Dr Svend Peterson-Mahrt at Cancer Research UK.