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Telomere instability and the formation and transmission of radiation induced DNA damage. (TELORAD), Final Report

Funded under: FP5-EAECTP C


Risk estimation for the induction of cancer by radiation in human populations is based on epidemiological data. Most of the extrapolations (at low dose, at low dose rate, partial exposure, etc.) are limited by their ignorance of the mechanisms of cancer induction. Large sets of data have been accumulated to determine the quality and quantity of radiation induced DNA damage. Loss of DNA repair capacity is often observed in radiosensitive individuals. When TELORAD started, many genes involved in DNA repair were identified and some of them were found to be involved in radiosensitive disorders. However the level of variation in individual response is so high that it may be expected that many other genes were to be discovered (some of them having been discovered meanwhile).
TELORAD is focused on specific candidate genes involved in DNA-repair and on genes involved in telomere maintenance and aims to advance their knowledge of the mechanisms underlying DNA damage processing and stabilisation and then transmission trough cell divisions, the first steps towards radiation-induced tumours.
TELORAD will address the question of the mechanistic link between these two process in mammalian cells (mice, hamster and human to determine the mechanistic link between telomeres, telomerase, telomere binding proteins and DNA repair genes and their respective roles in cellular radiosensitivity. Mechanisms of stabilisation of broken chromosome ends, a starting point in the transmission of radiation-induced damage, will be studied. Short telomeric arrays are also present at intrachromosomal locations, probably reflecting species evolution. The stability of these Interstitial Telomeric Sequences (ITS) will be studied. Long-term consequences, such as gene amplification will be investigated to identify the involvement of telomere maintenance in radiosensitivity of individuals.

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