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Telomere instability and the formation and transmission of radiation induced DNA damage

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Rodent models for telomere biology studies

Several mouse models have been produced for studying the involvement of telomeres in DNA repair, cancer and ageing processes.

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Found at the chromosomal ends, the specialised structures called telomeres are potentially responsible for tumour development and ageing effects. Focusing on telomere length and proteins as well as telomerase activity and DNA repair pathways, a EURATOM project developed a set of mouse models for further studies. These models involve various mammalian cells such as mice with genetic backgrounds lacking telomerase, PARP, ATM, DNA-PKs, Ku 80, double mutant mice, human or hamster cells over-expressing specific genes. They have been extensively used as tools to thoroughly study any relationship between the non-homologous end-joining pathway and telomere maintenance. More specifically, a unique murine model (Terc KO mice) has been generated that displays chromosomal instability due to extremely short telomere. Irrespective to any defects present in the DNA repair pathways, telomere shortening has been found responsible for increased radiosensitivity of cells. Additionally, research showed that two DNA repair proteins called Ku and DNA-PKcs are of primary importance for telomere capping process and telomerase activity. Particularly, the DNA-PKcs was found to be an important factor that contributes to sound cooperation of telomere maintenance with telomerase activity. The latter protein has been identified in the NHEJ DNA repair pathway, which is critical for telomere dysfunction in terms of detection, processing and signalling. Moreover, an innovative specialised technology called SKY/Q-FISH offers increased potentialities in identifying the role of telomeres in chromosomal aberrations.

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