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ROLE OF HISTONE MODIFICATIONS IN DNA DAMAGE RESPONSE IN MAMMALS

Objective

After DNA damage a signal must be created to recruit DNA repair factors to the lesion. Then the repair machinery needs to gain access to DNA and chromatin should be properly reassembled. DNA assembly with histones to form chromatin creates a physically limits the access to DNA. Alterations of chromatin that do not affect the DNA sequence constitute the epigenetic level of regulation of DNA metabolism. Among them, the post-translational modification of histones can directly regulate chromatin structure and they can also recruit different proteins to DNA serving as signaling and docking points. There is not much information regarding the role of these modifications in DNA damage response (DDR). This project looks forward to gaining insight into the role of histone H3K79 and histone H4K20 methylation in recuiting DNA repair factors. 53BP1 has been proposed to be recruited to the lesions by methylation of H3K79 and/or H4K20, although the mechanism is not still clear. In yeast, Dot1, the enzyme responsible for H3K79 methylation, is required for a normal DDR. As a second objective we would like to analyze the potential modifications of H3K56 in mammalian cells and determine if they have a function in DDR. Also in yeast, it has been described that H3K56 acetylation is necessary for the re-assembly of chromatin after repair. In mammals it seems that methylation of this residue takes place instead of acetylation. However the role of these marks has not been well studied in mammals. We will employ in vitro cell culture to analyze the exposure of these marks after DNA damage, the changes in localization or protein interactions of the enzymes responsible for them and to identify proteins that create or recognize these marks. Additionally KO mice will be used to analyze the physiological relevance of the results in vivo. All these studies are highly relevant to the EU, as they imply the interconnection of two priority fields in EU (both of them have a European Network).

Field of science

  • /natural sciences/biological sciences/zoology/mammalogy
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-IOF-2008
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Funding Scheme

MC-IOF - International Outgoing Fellowships (IOF)

Coordinator

FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Spain
Activity type
Research Organisations
EU contribution
€ 237 283,61
Administrative Contact
Dolores Liébanes (Ms.)