21. Link between telomere maintenance & DNA damage response mechanisms, and their role of individual radio-sensitivity. Insights on action of BRCA1 gene
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Abstract: Telomeres are physical ends of chromosomes responsible for chromosomal end protection. There is a strong inter-dependence between telomere maintenance and cellular mechanisms that regulate DNA damage response. At least 17 mammalian genes involved in DNA damage response have, so far, been implicated in telomere maintenance and it is likely that the number of these genes will grow. The results generated by Predrag Slijepcevic and his team provide additional support for the link between telomere maintenance and DNA damage response mechanisms. The most significant finding, perhaps, is the potentially direct involvement of BRCA1 in telomere capping function. BRCA1 is a known tumour suppressor gene. Telomere maintenance also constitutes a powerful tumour suppressor mechanism. BRCA1 defective cells may, therefore, have failures in two tumour suppressor mechanisms.
The exact mechanisms through which BRCA1 exerts its tumour suppressor properties are not fully understood. It is now of interest to investigate the possibility that BRCA1 may exert, at least in part, its tumour suppression through effects on telomere maintenance. This finding is also relevant from the perspective of radiation protection. BRCA1 defects cause radiosensitivity and previously demonstrated link between radiosensitivity and telomere dysfunction provided by Dr Predrag Slijepcevic and his team has now been strengthened.
In addition, a range of primary cell lines from 11 patients that over-responded to radiotherapy were used by Dr. Predrag Slijepcevic and his team to demonstrate further the inter-dependence between telomere maintenance and DNA damage response mechanisms.
Collectively, above results provide support for the hypothesis that that telomere maintenance mechanisms and mechanisms of DNA damage response are tightly linked. A direct prediction from this hypothesis is that telomere maintenance may serve as a useful indicator of individual radiosensitivity and further research is required to test this link more stringently.