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In cells where DOT1L gene is defective, restart of transcription after UV exposure doesn’t occur (black dots represent mRNA which are witnesses of the cell transcriptional activity).
PLoS Genet Jul 2013
Proc Natl Acad Sci U S A June 18, 2013
July 4, 2013
Frédéric Coin and Jean-Marc Egly’s team at IGBMC sheds a new light on the restoration of transcription after prolonged UV exposure causing damages to the DNA. They reveal new elements of the pathophysiological processes involved in Cockayne syndrome. Their results are published June 3 and July 4 in the journals PNAS and PLoS Genetics.
Without protection against sunlight, UV radiation can cause damage to the DNA and occasion lasting changes in the genetic code. To avoid these mutations to spread and prevent the occurrence of cancer, a complex system suspends cellular life while the genome is repaired. During 2 to 3 hours after DNA damages, the activity of the cell is dramatically slowed down. About 90% of cell transcriptional activity, this particular step while DNA is transformed into messenger RNA and finally into protein, is abolished. This period of time is necessary for DNA repair.
While the molecular mechanisms involved in the repair of UV damages are now well documented, the processes implied in the inhibitions and restorations of gene expression after UV exposure remain poorly understood. Two publications from F. Coin and JM. Egly’s team shed a new light on these processes. First, the researchers highlight the role of ATF3 protein in the inhibition of transcription. Following DNA damage, ATF3 binds to the promoters of genes, blocking access to any cellular machinery and thereby preventing the gene transcription into RNA. When the damages are repaired and transcription can carry on safely, it is the arrival of the CSB protein that allows the transcription to start again.
These results provide new evidence for the understanding of mechanisms that regulate the restart of transcription in response to DNA damage, as well as pathophysiological processes involved in Cockayne syndrome. It opens new therapeutic perspectives in the treatment of cancer. For example, a DOT1L inhibitor could potentiate the effects of current treatments, leading cancer cells to apoptosis in response to DNA damages caused by chemotherapy.