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Epigenetics and DNA repair. Is a chromatin remodeling process involved in the higher UV sensitivity of nucleotide excision repair defective cells?

Final Report Summary - EPINER2007 (Epigenetics and DNA repair. Is a chromatin remodeling process involved in the higher UV sensitivity of nucleotide excision repair defective cells?)

During the second half of 2010 it has been established molecular biology techniques learnt during the Incoming Phase of the MC project (IIF-221362) in the New Laboratory of Epigenetics and Genomic Instability recently created in our Institution, with the aim to analyze histone tail modifications during repair of DNA lesions induced by ultraviolet irradiation (UV) in normal and DNA repair deficient cell lines (either from hamster or human origin).

Brief General Introduction

Formerly, it was believed that histones proteins were only responsible for packaging DNA into the cell nucleus. However, during last two decades, the knowledge about the possibility of regulating gene expression by modifying DNA-histone interactions through changes or modifications at histone tails levels, become of the utmost importance since it has been discovered that in the development of several cancer and neurodegenerative diseases histone modifications can occur.

In the base of these diseases have also been found deficiencies in DNA repair mechanisms. In this respect, two human syndromes (Xeroderma Pigmentosum and Cockayne's Syndrome) affecting one of the major DNA repair systems in human cells called nucleotide excision repair or NER, characterized by sensitivity to UV irradiation, become an interesting model to contribute to unravel the link between chromatin remodeling processes and DNA repair.

The most frequent histone tail modification is the histone acetylation/deacetylation process. Histone acetylation and deacetylation are controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs) determining either gene activation or inactivation, respectively. Acetylated histones could enhance chromatin accessibility through the loss of negative charges due to acetylation of terminal lysines hindering the attractive force between the nucleosome core and negatively charged DNA. In this respect, we have previously demonstrated in Chinese hamster chromosomes regions enriched in acetylated histone H4 are preferred sites for radiation-and endonucleases induced chromosome lesions (Martínez-López et al., 2001; Martínez-López and Di Tomaso, 2006; Martínez-López et al., 2007).
Expected results on the possible influence of chromatin remodeling processes to the higher sensitivity to UV radiation of Cockayne's Syndrome cells will lead to perform furthers investigations to understand how these mechanisms are involved in the development of cancer and/or neurodegeneration found in these patients.

In this respect, we have recently shown (Martínez-López et al., 2010) that the failure in the NER sub-pathway called transcription coupled repair (TCR), which characterise the molecular base of the Cockayne's Syndrome (CS), seems not to be responsible for the increased frequency of genetic damage observed in CS simile cells exposed to UVC, since UVC-induced chromosome lesions were distributed more random in CS cells than in normal ones instead of being concentrated on the transcribed chromosome regions as expected (Paper is included in deliverables).

A detailed description of academic and research activities carried out during last year of the MC project as well as a complete overview of relevant results obtained during the whole MC project have been included in the attached files.