Objective
A wealth of information has accumulated on the role of pS3 as a gene product required for blocking the progression of cells in the G1 phase of the cell cycle in response to DNA injury. However, few data exist on how DNA damage results in pS3 activation, and even the activation mechanism per se is still poorly documented. The main objective of this project is to study the involvement of DNA-dependent kinase (DNA-PK) in the pS3 activation by DNA damage. Most conditions used to induce pS3 (i.e.: UV-light or gamma irradiations) have the inconvenience that they produce a varied scale of DNA modifications and mutations that could interfere in this study. We have therefore designed a strategy based on the use of the highly specific endonuclease encoded in the intron of S. cerevisiae 21S rRNA gene: I-Sce I. Its recognition site should occur only once in a genome whose size is approximately 20 times as large as the human haploid genome. In a first step, the introduction of such a target sequence in a reporter vector containing pS3 binding sites should allow us to directly link the occurrence of double strand breaks with pS3 activation as a transcription factor. In a second step, we would like to demonstrate that p53 is activated by a post-translational mechanism involving its amino-terminal phosphorylation by the aforementioned DNA-PK which is targeted to anomalous DNA structures (double strand breaks, gaps, bubbles or cruciform structures) by a 70/80 kDa heterodimer known as Ku autoantigen. The introduction of pS3 amino-terminal domain, through transfection or microinjection experiments in induced cells, either defective in Ku 80 protein or normal, should give rise to negative dominant interactions and thus prevent p53 activation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics genomes
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Coordinator
34293 MONTPELLIER
France
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