EPINER2007 · Epigenetics and DNA repair. Is a chromatin remodeling process involved in the higher UV sensitivity of nucleotide excision repair defective cells?
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2008-05-14 → 2010-05-13
- Финансиране от ЕС
- 233 872 €
- Участници
- 1
- Схема
- MC-IIF
Линиите свързват координатора с партньорите.
Накратко на български
Епигенетичните процеси и промените в структурата на хроматина се анализират при клетки, увредени от UVC лъчи. Това помага да се разбере как разгъването на ДНК влияе върху способността на клетката да поправя генетичните си увреждания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Epigenetics and DNA repair. Is a chromatin remodeling process involved in the higher UV sensitivity of nucleotide excision repair defective cells?
Summary of objectives and research activities carried out in the frame of the incoming phase of MC project The main goal of our MC project was to study the influence of chromatin remodelling in the processing of UVC-induced lesions, employing as a cellular model, Chinese hamster cell lines proficient and deficient in transcription coupled repair from the nucleotide excision repair system. In the first part of the MC project we were concentrated on the analysis of the distribution of UVC-induced lesions at the chromosome level in mutant and normal cells. Contrary to expectation less chromosome lesions were observed in transcribing regions of the DNA repair deficient cells with respect to normal ones. In order to test if this result could be related to a different response in terms of chromatin remodelling after UVC-irradiation, a chromatin decondensation process was studied at different recovery times after UVC-irradiation in both cell lines employing an in situ nick translation technique. Both cell lines showed a peak in chromatin decondensation after 2 h of UVC-irradiation and in both cases this decondensation process was accompanied by an increase on histone acetylation (an epigenetic marker of chromatin decondensation controlled by acetyltransferases and deacetylases enzymes). During the second half of the MC project, we have concentrated on studying how changes in the histone acetylation pattern could influence the processing of DNA lesions induced by UVC by using a histone deacetylase inhibitor like trichostatin A or TSA. Survival assay showed that normal cells can behave as Cockayne syndrome simile cells when they are exposed to trichostatin A previous to UVC-irradiation. Moreover, DNA primary lesions are not removed after 24 h of UVC irradiation in the presence of TSA. Finally, the application of the microccocal nuclease digestion assays evidenced a differential nucleosome array when cells were previously exposed to TSA before UVC-irradiation. These results could indicate that an imbalance in the histone acetylation levels could change recognition sites for DNA repair, interfering with the correct interaction between repair proteins and DNA lesions immersed in the modified chromatin structure. The appropriate knowledge of how epigenetic changes interact with the machinery responsible for the removal of induced DNA lesions could help, for example, to sensitise tumour cells to classical chemotherapy and radiotherapy treatments. On the hand, several neurodegenerative syndromes could have a molecular base related to epigenetic changes as it seems to be the case of Cockayne syndrome as our data is suggesting.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The knowledge on regulatory roles of epigenetic mechanisms (heritable changes in the genome function without a change in the DNA sequence) has grown very fast during the last decade since they can be the target for treating several pathologies related to cancer and neurodegeneration. 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, characterized by sensitivity to UV irradiation, become an interesting model to contribute to unravel the link between chromatin remodeling processes and DNA repair. 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 further investigations to understand how these mechanisms are involved in the development of cancer and/or neurodegeneration found in these patients. Since the proposed investigation require a multidisciplinary study (cytogenetics, molecular biology and immunocytochemestry), it will become of the utmost importance not only for the research activity planned to carry out at the Laboratory of Prof. Palitti, since this line of research fits very well with the purposes already established by the Network of Excellence (NoE – Epigenetic Network created by several laboratories from Europe) supported by the FP6 program from the European Community; but also for having the possibility to incorporate new methodologies and strategies to continue with the study of possible links between epigenetic and DNA repair in our laboratory in Uruguay with the aim to initiate studies on epigenetic therapy mainly applied to facilitate chemotherapy treatment of cancer diseases.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITA DEGLI STUDI DELLA TUSCIA · ViterboКоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз