Embedded at the end of chromosomes are structures called "telomeres" that in normal cells become shorter as cells divide.

As the shortening progresses it triggers cell proliferation arrest or death.

Cancer cells adopt different strategies to overcome this control mechanism that keeps track of the number of times that a cell has divided.

One of these strategies is the alternative lengthening of telomeres (ALT) pathway, which guarantees unlimited proliferation capability.

Now, a research group led by Claus M. Azzalin at Instituto de Medicina Molecular João Lobo Antunes has discovered that a human enzyme named FANCM is absolutely required for the survival of ALT tumour cells.

The results were now published in the open access journal Nature Communications.

Future strategies targeting the activity of this molecule in ALT tumour cells can constitute the basis of a novel therapeutic protocol for the treatment of these tumours.

ALT tumours are approximately 10% of the human tumours, and often develop in children and they are particularly resistant to conventional chemotherapy.

"Contrary to the canonical telomere elongation mechanism that activates the enzyme telomerase, these tumour cells specifically use this alternative pathway which is insensitive to therapeutic approaches based on telomerase inhibition", explains Claus M. Azzalin, group leader at iMM.

"Previous studies have shown that a sustained physiological telomere damage must be maintained in these cells to promote telomere elongation. This scenario implies that telomeric damage levels be maintained within a specific threshold that is high enough to trigger telomere elongation, yet not too high to induce cell death", says Bruno Silva, first author of this work.

Using a series of molecular biology-, cell biology- and biochemistry-based experiments, the research team found an essential role for FANCM, a component of the DNA damage repair machineries of the cell.

"What we have found is that ALT cells require the activity of the FANCM in order to prevent telomere instability and consequent cell death", says Bruno Silva.

"When we remove FANCM from ALT tumour cells, telomeres become heavily damaged and cells stop dividing and die very quickly. This is not observed in tumour cells that express telomerase activity or in healthy cells, meaning that is a specific feature of ATL tumour cells", explains Claus M. Azzalin.

"In our view, this is very exciting because it indicates that transiently drugging FANCM activity in ALT cells should lead to very fast cell death specifically in these cells, and sets the potential basis for an alternative therapeutic protocol for this type of tumours", adds Claus Azzalin.

Source: Instituto de Medicina Molecular