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Transcription defects implicated in the disease of children of the moon

In wild cells, the interaction of the DNA repair factor XPC with the transcription factor E2F1 allows recruitment of the ATAC complex. This succession of events leads to the acetylation of histone H3 and the transcription of genes. In patient cells, in the absence of XPC, the ATAC complex is no longer functional and genes are not expressed

XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1.

Bidon B(1)(2)(3)(4), Iltis I(1)(2)(3)(4), Semer M(1)(2)(3)(4), Nagy Z(1)(2)(3)(4), Larnicol A(1)(2)(3)(4), Cribier A(5), Benkirane M(5), Coin F(6)(7)(8)(9), Egly JM(10)(11)(12)(13), Le May N(14)(15)(16)(17).

Nat Commun July 4, 2018


July 4, 2018

Children of the moon cannot be exposed to the sun because of their deficiency in DNA repair proteins including XPC, the factor that recognizes ultraviolet damage. However, this failure is not enough to explain all their symptoms. In this study, researchers from Frédéric Coin's team, including Nicolas Le May, (CNRS / Inserm / University of Strasbourg) showed that the XPC factor was also involved in a fundamental mechanism of gene expression, transcription. These results are published on July 4, 2018 in the journal Nature Communications.


Xeroderma pigmentosum is a genetic disease that can result from a mutation in the gene coding for the XPC protein, a DNA damage sensor that recognizes lesions produced by ultraviolet rays. Patients who are very sensitive to the sun have an increased risk of skin cancer but also develop neurological or ocular disorders. These symptoms, originally associated with defects in DNA repair, may also be related to disturbances in transcription, a fundamental mechanism of gene expression. Frédéric Coin's team therefore sought to establish the link between the XPC factor and transcription.

 

In normal cells, the researchers observed the presence of XPC on nearly 500 genes. The XPC occupancy sites on DNA coincide precisely with those of RNA polymerase II, the enzyme that catalyzes transcription. On the other hand, in cells derived from patients in whom XPC is defective, they showed that the expression of these genes was deregulated and that RNA polymerase II was no longer recruited correctly on their promoter, thus highlighting the link between the XPC factor and transcription.

 

The researchers then analyzed histone modifications that are essential to the development of an ideal chromatin environment for gene expression. They were particularly interested in the acetylation of histone H3, mediated by two major transcription complexes, SAGA and ATAC. The researchers observed that the acetylation of histone H3 in the 500 genes targeted by XPC was deficient in its absence. This is explained by the fact that XPC interacts with the ATAC complex and allows its recruitment on genes. Finally, they showed that the XPC protein was specifically recruited from the 500 genes through its interaction with the E2F1 protein, a transcription factor recognizing particular DNA sequences present upstream of the promoters of the 500 genes. Thus a succession of events, initiated by the recruitment of the transcription factor E2F1 followed by the arrival of XPC and the recruitment of ATAC on specific genes leads to the remodeling of chromatin and the expression of these genes.

 

These results establish that in addition to repairing DNA, XPC regulates transcription, and provide a better understanding of the molecular basis of defects in patients with Xeroderma pigmentosum.


This study was funded by ANR, the Cancer Research Association, Korea's National Research Foundation, the National League Against Cancer, the Foundation for Medical Research, and the South Province Research Incentive Award in New Caledonia.


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