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New protein efficently cleans DNA breaks during chemotherapy

An international group of researchers, with the participation of the members of the University of Seville and the Andalusian Centre of Molecular Biology and Regenerative Medicine (CABIMER), have described a new methodology for making tumour cells behave when submitted to chemotherapy.

The research was published in Science this month, with the developments contributing to the fundamental tools available in the fight against cancer.

An important group of anti-tumour agents base their effectiveness on the induction of breaks in DNA, which preferably affects the growth and survival of tumour cells.

The DNA breaks produced by these agents are characterised by the fact that they contain protein blocks that need to be eliminated from the edges of the break to allow the damage to be repaired, so reconstituting the integrity of the genetic material.

That is to say, the breaks have to be "cleaned" before they can stick together again, which is essential for guaranteeing cell function and survival.

Therefore, the mechanisms that clean these breaks, both in the tumour as well as in the healthy tissue, largely determine the cellular response to these agents, and, in this last instance, the effectiveness of the treatment and its secondary effects.

"Until now, it was thought that for the edges of the breaks to be cleaned, it was necessary for there to be a step in which the protein block is degraded, leaving small amounts of residue, which are later removed using a highly specialised enzyme called TDP2, and which we discovered in 2009. In this project, we have shown that the breaks can be cleaned directly, without any need for degradation, by means of application of ZATT, a new protein that we have identified and which has the ability to restructure and modify the edges of the break to facilitate the activity of TDP2", reports one of the authors of the study, the CSIC researcher Felipe Cortés Ledesma.

In summary, the experts indicate a new way via which cells can respond to chemotherapy.

This knowledge has to help constitute the basis for future tools as well as the prognosis of therapeutic interventions.

On one hand, the functionality of this method can be used to predict the response of the tumour to chemotherapy, which can help with the stratification of patients and the design of personalised treatments.

On the other hand, new molecules that inhibit the TDP2-ZATT route could be used to increase the sensitivity of tumours to these treatments and avoid the development of possible resistance.

Source: University of Seville



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