//
you're reading...
Cancer, DNA

An alternative path to immortality

In December 2015, David Clynes (a postdoc in Richard Gibbons’ lab) was awarded a 5-year fellowship from Children with Cancer to set up his own research group. Here, his colleague and co-author Barbara Xella describes the work that was instrumental in obtaining this funding, published in Nature Communications last year.

Chromosomes are long DNA molecules wrapped up around a protein scaffold, whose ends contain arrays of repetitive pieces of the DNA code called telomeres.

Telomeres are important structures that stop the delicate chromosome ends from being damaged and worn away, thus protecting the genetic code that is essential for life.

Chromosomes

Each human cell has 23 pairs of chromosomes. Image credit: Female Karyotype by Hey Paul Studios via Flickr.

However, with every round of DNA replication telomeres become a little shorter, until eventually the DNA molecule is exposed and damaged, leading to the death of the cell.

Telomeres therefore dictate not only the aging rate of individual cells, but ultimately of our entire body.

As a result, the shorter the telomeres, the older the cell – but when it comes to telomeres, a little goes a long way.

Cells which are actively growing and dividing maintain an adequate telomere length thanks to the long and repetitive nature of the telomere itself, which means the cell can afford to lose a repeat or two every time it divides. But at some point telomeres will reach a critical minimal length, signalling that the cell is too old to keep going.

However, some cancer cells hijack systems to maintain long telomeres throughout hundreds of rounds of cell division, thereby becoming “immortal”. These immortal cells continue to grow and divide endlessly, eventually forming a tumour.

Thus, a deadly paradox emerges: immortal cells, instead of allowing us to live forever, cause us to die sooner.

There are two known methods which cancer cells exploit in order to maintain the length of their telomeres. Most cancers activate an enzyme called telomerase which adds repeats to chromosomal ends. Telomerase expression is normally tightly regulated during development: it is highly active during the early stages of life when cells are busily dividing to produce all the different tissues of the body, and it becomes silenced in most cells once the organism is fully formed and its cells are no longer required to grow rapidly.

However, a subset of cancers uses a different mechanism to maintain telomeres: the Alternative Lengthening of Telomeres pathway (otherwise known as ALT). ALT cancers exchange telomeres between chromosomes using homologous recombination, a process normally required to repair damage to the DNA.

Although the ALT pathway is only active in around 15% of cancers, these include some of the most clinically challenging to treat, such as brain cancers, bone cancers and lung cancers. Targeting ALT is very important in the development of novel therapies for these devastating diseases.

David Clynes, a post-doc in Richard Gibbons’ lab at the WIMM, has recently published a paper in the journal Nature Communications in which he explores a potential pathway that may lead to specifically targeting ALT cells.

The Gibbons lab is interested in studying a protein called ATRX, which has been shown to be mutated in ALT cancers. To be precise, inactivation of ATRX seems to be necessary, albeit not sufficient, to trigger ALT and therefore tumour development.

David and his co-workers found that re-expressing ATRX in cancer cells in which the ALT pathway is active leads to ALT suppression, They provide evidence that this suppression may be linked to a role for ATRX in regulating how DNA is packaged at telomeres, and preventing the formation of unusual 3Dstructures within the telomere DNA which could trigger the ALT pathway.

These detailed findings highlight a new mechanism that could potentially be used to treat aggressive forms of this disease that currently evade many treatment strategies.

Cancer cells may well have worked out how to achieve immortality – but thankfully, we now understand enough about how they accomplish this terrifying feat that we can start trying to find ways to stop them.

Sign up to alerts from the blog in order to keep up to date with David’s research, and other cutting-edge science from the MRC WIMM.

Post edited by Bryony Graham and David Clynes.

Discussion

One thought on “An alternative path to immortality

What do you think?

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Enter your email address to follow the WIMM blog and receive notifications of new posts by email.

Monthly archive

Follow the MRC WIMM on Twitter

%d bloggers like this: