Paris, 12 April 2010
Repairing damaged DNA…
The human organism has developed a number of strategies to protect and maintain its genetic code. The harmful effect of physical and chemical mutagens causes lesions in the DNA and disturbs genetic coding. If efficient repair systems do not respond to the lesions, they will cause mutations leading to cancers and ageing. Jean-Marc Egly carried out research several years ago that led to the discovery (by identifying the TFIIH factor) of the relationship between the gene reading mechanism and the DNA repair mechanism named NER (nucleotide excision repair) that guarantees genetic stability (see illustration below).
© Myriem Belkacem - Inserm
NER (nucleotide excision repair) action mechanism
DNA damaged as a result of exposure to chemical or physical mutagens (UV radiation, etc.) takes on a particular form recognised by the NER complex. When the latter starts to work, it eliminates the damaged DNA fragment and replaces it with a healthy one.
Due to this discovery, diseases involving alternation of DNA repair mechanisms will now be better understood. This is the case for the “children of the moon” who suffer from xeroderma pigmentosum, a rare genetic disease characterised by extreme sensitivity to sunlight and a very high risk of skin cancer. The disease has been linked to mutations in eleven of the genes involved in repair mechanisms. The mutations themselves are however insufficient to explain the neurological symptoms and developmental disorders found in more than a third of the persons with the disease.
The researchers thus formulated a hypothesis: the various factors implicated in DNA repair appear to have functions beyond the role already described.
…and regulating transcription
For the new study, researchers were interested in the operation of NER in conditions where DNA is not exposed to mutagens. In this case, data gathered by IGBMC's team reveals that various factors in the NER complex regulate RNA gene transcription. Each of the factors is involved in the mechanisms to modify the chromatin to prepare the starting point of RNA synthesis for transcription. Without these factors, transcription will be very limited.
Depending on the exact location of NER, repair and transcription functions will be activated. For Jean-Marc Egly, research director at Inserm, “This discovery explains the variety of symptoms observed in xeroderma pigmentosum. It also represents a big step forward in understanding “epigenetic” mechanisms which regulate genetic coding and prevent genes from proper coding in the right place at the right time.”
NER factors are recruited to the promoters of activated genes and help chromatin modifications for efficient transcription in the absence of exogenous genotoxic attack
Nicolas Le May-1,3, David Mota-Fernandes-1,3, Renier Vélez-Cruz-1, Izarn Iltis-1, Denis Biard-2 and Jean Marc Egly-1
1-Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France
2-INSERM U602/CEA-IRCM, Hôpital Paul Brousse 12-16 Avenue Paul Vaillant Couturier 94807 Villejuif Cedex, France
3-These authors contributed equally to this work
Molecular Cell, April 2010
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