Chromosomal ends have protective structures named telomeres that distinguish them from broken chromosomes. Telomeres are composed of tandem G-rich DNA repeats bound to an array of proteins that are essential for telomere capping. The synthesis of telomeres by telomerase and their function are proposed to be biological determinants in the process of cancer and aging. Telomere dysfunction because of short telomeres or mutation of telomere-binding proteins can lead to chromosomal end-to-end fusions and loss of cell viability. I will test the relevance of telomeres and telomerase in tumour development and aging using mouse models deficient for proteins that are important for telomere function, such as telomerase (Tere knock-out mice) and telomeric binding proteins (Ku86 and DNA-PKcs knock-out mice). Further I will study transgenic mice overexpressing the catalytic subunit of telomerase (mTert) in adult tissues that normally lack telomerase to directly analyse the impact of telomerase upregulation for tumour growth and ageing. I will test whether telomerase cooperates with loss of p53 in tumorigenesis using telomerase transgenic p53 knockout mice. Additionally I will evaluate the role of telomeres and telomerase in tumourigenesis by analysing double mutant mice lacking telomerase, with an activatingCdk4 R24C mutation, present in human hereditary melanoma. The analysis of these different mouse models should help to understand the function of telomerase intelomere maintenance, cancerogenesis and age-associated diseases.
Field of science
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /natural sciences/biological sciences/genetics and heredity/mutation
- /medical and health sciences/clinical medicine/cancer
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