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AFT3, a new target for cancer treatment

Over the course of a cell's life those endure many stresses, some of which result in DNA damage. To have time to repair these lesions, cells inhibit fundamental processes including transcription, a mechanism that allows gene expression. Frédéric Coin and Jean-Marc Egly’s team at the IGBMC showed that the degradation of the AFT3 protein is essential to restart the transcription once the lesions are repaired. This discovery may optimize certain chemotherapies based on the mechanism of stress. These results are published in the journal Molecular Cell on December 7, 2017.

When lesions are detected, cells stop house-keeping mechanisms, such as transcription. However, to allow DNA repair, some genes continue to be expressed. This is the case of the CSA and CSB genes coding for proteins known to promote repair following DNA damage. In Cockayne syndrome, a rare genetic disorder characterized by photosensitivity and neurological abnormalities, these genes are mutated.

To better understand the mechanisms involved in the recovery of transcription after stress, Frédéric Coin and Jean-Marc Egly's team, in collaboration with Vincent Laugel's team at the University of Strasbourg, studied cells from patients with Cockayne Syndrome. They observed that a protein, called ATF3, is rapidly expressed as a result of DNA damage caused by ultraviolet (UV) rays and inhibits the transcription of approximately 70% of genes present in CSA and CSB deficient cells.

To restart transcription, cells must get rid of the ATF3 protein. The researchers found that CSA and CSB proteins were essential for the elimination of ATF3. An important discovery that explains why the resumption of transcription cannot operate in patients with Cockayne syndrome, where the CSA and CSB genes are mutated and therefore AFT3 is not degraded.

Understanding this mechanism opens the way to new therapies targeting the AFT3 protein. Many chemotherapies rely on the same mechanism as UV stress to cause cell death. But cells challenge this mechanism by repairing lesions generated on the DNA. Using, in addition to chemotherapy, molecules that prevent the elimination of lesions or the return of gene expression, for example molecules that would inhibit the degradation of ATF3, could improve these anti-cancer treatments.

The study was funded by the ANR, ERC, ARC Foundation, National Cancer Institute, Korean National Research Fund for International Collaboration and the Italian Telethon.

Illustration: Degradation of ATF3 in normal cells versus absence of degradation in CS cells