Cell memory loss may trigger cancer

A family of enzymes may trigger cancer by causing loss of cell memory, according to a new report¹ from Cancer Research UK and Babraham Institute scientists.

Every time a cell divides, it has to remember which of its many thousands of genes are switched on or off at the time. If that memory is impaired, the resultant cells do not remember what sort of cells they are supposed to be. Such lack of differentiation is a key factor in cancer.

Scientists at Cancer Research UK’s London Research Institute and the Babraham Institute in Cambridge have now shown that certain enzymes can alter this genetic memory. Evidence of this interference was present in a large proportion of tumours, strongly implicating the enzymes in the development of cancer.

Control of gene expression – switching genes on or off – is a fundamental aspect of cell regulation. Retaining the memory of which genes are switched on and which are switched off is called epigenetics. One of the most common epigenetic mechanisms is methylation of the DNA, which switches genes off. This marker on the genetic code also acts as a physical reminder that the gene is meant to be switched off.

Mistakes or changes in the location of these markers can have direct effects on regulating regions, which can induce cancerous growth.

The researchers discovered that AID², an enzyme that generates essential genetic variation in the immune system, can also alter the methylation in DNA. This could leave cells with inaccurate memories, leading to cancer.

Dr Svend Petersen-Mahrt, senior co-author of the paper, says: “This is the first detailed study to show that the AID enzyme can act on methylated DNA.

“AID chemically alters the methylated DNA by mutating it. Cells have ways to repair such mutations, but in this case, when the cell repairs the DNA, it is left unmethylated and the cell’s memory of the gene’s ‘off’ status is lost.

“When AID acts in an uncontrolled fashion on a key gene, this gene will be switched on in the wrong place or at the wrong time. This could interfere with the usual control of cells’ behaviour, leading to the development of cancerous traits such as uncontrolled growth.”

The researchers looked for characteristic alterations in colon cancer genes, and found that in a substantial number of tumours, similar mutations to those caused by AID were present.

Dr Wolf Reik, based at the Babraham Institute and senior co-author of the report, adds, “If we can now show that these mutations were caused by AID or other members of that family, it will strongly suggest that these enzymes are a major contributor to the development of cancer.”

The study was also the first to find AID in stem cells and germ cells.

Dr Reik adds, “We know that AID’s normal function is to help the immune system develop. It was surprising to find AID in stem cells as well. We think it has a role early on in development, determining which genes will be switched on or off in each cell.”

The research groups will continue to explore the role of AID in cancer and epigenetics. The mechanisms of epigenetics can be exploited by scientists to turn mature cells back into stem cells. Learning how to control expression of these enzymes and where they act could therefore help in the development of stem cell and cloning therapies, as well as improve our understanding of cancer.

Dr Lesley Walker, Director of Cancer Information at Cancer Research UK, says, “The mechanism of genetic alteration that this research has uncovered may underlie the molecular basis of a substantial proportion of cancers.

“Every advance in our understanding of the causes of cancer puts us in a better position to improve ways of detecting and treating the disease.”

ENDS

Journal of Biological Chemistry

1. Activation-induced cytidine deaminase