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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).

Histone Methyltransferase DOT1L Drives Recovery of Gene Expression after a Genotoxic Attack.

Oksenych V, Zhovmer A, Ziani S, Mari PO, Eberova J, Nardo T, Stefanini M, Giglia-Mari G, Egly JM, Coin F.

PLoS Genet Jul 2013

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress.

Kristensen U, Epanchintsev A, Rauschendorf MA, Laugel V, Stevnsner T, Bohr VA, Coin F, Egly JM.

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.

In the absence of CSB, ATF3 represses transcription well after the DNA damages are repaired. Essential to the success of transcription process coupled with DNA repair after UV radiation, the CSB protein is also known to be responsible for Cockayne syndrome when its gene is mutated. This rare genetic disorder is characterized by impaired growth, a progressive degeneration and a very short lifespan (between 10 and 20 years depending on the different forms of the disease). These patients present accelerated aging due to their hypersensitivity to sunlight which prohibits them from any exposure to radiation. This work provides new information for the understanding of this disease and have been the subject of an article in the journal PNAS, June 3, 2013.

In a second study, published in the journal PLoS Genetics on 4 July 2013, researchers reveal the involvement of a new operator in the restoration of transcription after prolonged exposure to UV radiation. They demonstrate the essential role of the gene encoding the histone methyltransferase DOT1L. The DOT1L protein regulates the activity of histone H3, which is itself involved in the packing of DNA. Through the addition of a few atoms of carbon and hydrogen, DOT1L changes the histone H3 structure: it releases the DNA to which it is attached, making it accessible to the  transcription cellular machinery. When DOT1L is missing, restoration of transcription after genotoxic attack doesn’t occur anymore. These findings suggest that DOT1L is involved in maintaining an open chromatin structure, allowing the arrival of the cellular machinery required for the transcription to start again after the repair of DNA damage.

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.

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