Turning up the volume on silenced genes

Researchers at the Fox Chase Cancer Centre,
Philadelphia, USA, have elucidated the mechanism behind one form of gene silencing, which may open up a new route to cancer treatment.

During the development of healthy cells, genes that no longer need to be expressed are selectively 'switched off', or silenced,
through methylation — the addition of a chemical group to specific DNA bases. However,
aberrant gene silencing through this process can switch off essential genes and
cause cells to become cancerous.

Some cancer drugs already work through
demethylation, but this process is non-specific, which can cause side effects
and other problems, Dr Alfonso Bellacosa, an associate professor at Fox Chase,
explained. Using a specific process it could be possible to turn on incorrectly
silenced genes, leading to potential cancer therapeutics that target the
mechanisms underlying cancer development.

While it has been known for a number of
years that cells use methylation to silence genes, it has not been clear how
this is managed — how unmethylated regions are protected from unwanted
methylation, and how unwanted methyl groups are removed. This research, published
in Cell, has linked the process with an enzyme usually used in DNA repair, thymine
DNA glycosylase (TDG).

The team, including scientists from France,
Italy, and the USA, selectively inactivated TDG in mice; a change that proved lethal
for a number of the resulting mouse embryos. Genetic analysis of those that did
not survive showed disordered DNA methylation.

The researchers concluded that TDG was required
for normal embryo development, because it established correct patterns of
methylation in the specific regions of DNA that allow gene expression. TDG, along
with others, including a damage response protein, protects DNA from methylation
as well as specifically demethylating it.

'Since we now know there are proteins that
actively affect demethylation, then we can imagine a new type of cancer therapy
that demethylates specific genes. We would have a more precise and more
targeted type of therapy', said Dr Bellacosa.

The technique could also have potential in
other disorders caused by changes in DNA methylation, but it is still in its early stages and the next step will be to work out how to target specific genes
for demethylation.

'This is a very fundamental study that gets
at the process by which genes are turned on or turned off', Dr Bellacosa added. 'We
may be several years away from taking full advantage of this new knowledge. But
we will get there'.