19. Impact of telomere dysfunction on the cellular and organismal response to radiation and genotoxic agents
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Abstract: In the past, Maria Blasco and her team (partner CNIO) have shown that mice with critically short telomeres are highly sensitive to ionising radiation, i.e. show increased chromosomal instability upon gamma-irradiation. More recent results from a close collaboration between partners UAB and CNIO shed light on the mechanism underlying telomere-driven radiosensitivity. It was found that short telomeres re-join to double strand DNA breaks (DSBs), which in turn impairs proper DSB repair and, consequently, increases radiation-induced chromosomal instability.
This finding may be important for understanding the increased radiation sensitivity associated with age in humans, as well as provide a rationale for inter-individual differences to cytotoxic effects of radiation-based cancer therapy. In addition, partner CNIO found that mice with short telomeres were also hypersensitive to the alkylating agent MNU and oxidative stress. Together, these findings demonstrate a generalized hypersensitivity of mice with short telomeres to genotoxic agents and indicate that telomerase inhibitors may be combined with radiotherapy or other genotoxic agents to sensitise cancer cells to die. Related to this, partner CNIO is participating in ongoing studies on porphyrin-based telomerase inhibitors. Finally, partner CNIO contributed to studies showing that functional telomeres are important in mammalian meiotic synapsis and recombination. Of note shortened telomeres of late-generation telomerase-deficient mice impair meiotic synapsis and decrease recombination, in particular, in females. In response to telomere shortening, male germ cells mostly undergo apoptosis, whereas female germ cells preferentially arrest in early meiosis, suggesting sexually dimorphic surveillance mechanisms for telomere dysfunction during meiosis in mice. These findings might be of relevance for our understanding of sex-specific differences in radiation sensitivity.
More recently, using mouse models deficient for telomerase and the Ku86 telomere-binding protein, the CNIO team has performed a complete transcriptome analysis to assess the global effects of telomere shortening or telomere dysfunction in male germ cells. The transcriptional profile of germ cells with severe telomere shortening was similar to that of Ku86-deficient cells, suggesting that short telomeres trigger a DNA damage response similar to that triggered by Ku86 deficiency. The combination of short telomeres and Ku86 deficiency had an accumulative effect on the same set of genes.
In keeping with the particular importance of stem cell proliferation and differentiation for the outcome of radiotherapy, partner CNIO has participated in studies evaluating the impact of telomerase shortening on the stem cell compartment. The obtained results indicate that telomerase is required for differentiation of adult bone marrow stem cells. Interestingly, telomere attrition and the ensuing chromosomal instability dramatically impaired the in vitro proliferation of adult stem cells but did not affect the in vitro proliferative potential of embryonic stem cells. More recently, the CNIO team has determined the role of both telomerase and telomere length on epidermal stem cell behavior. In particular, mice with critically short and dysfunctional telomeres showed a defective mobilization of epidermal stem cells, which anticipated the fact that these mice are resistant to skin tumorigenesis protocols and show a premature aging of the skin. In turn, mice that over-expressed telomerase in the skin showed an augmented stem cell mobilization, also anticipating the fact that these mice are more prone to tumorigenesis.
In a further project, partner CNIO investigated whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance. CNIO found that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and non-hematopoietic (germ cells, fibroblasts) Fancg null cells display normal telomere length, normal telomerase activity and normal chromosome end-capping, even in the presence of extensive cytogenetic instability induced by radiation. In addition, early-passage primary fibroblasts from FA patients of complementation group G as well as primary human cells with reduced FANCG expression (FANCG-shRNA IMR-90 knock-down cells) showed no signs of telomere dysfunction. These data, which show that accelerated telomere shortening in FA patients is not due to a role of FANCG at telomeres but rather a consequence of the disease, suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia, by preserving their telomere reserve in the context of the disease.