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How spontaneous telomeric fusions occur: unravelling new pathways required for end protection

Objective

Telomeres are DNA-protein complexes that reside at the end of the chromosomes. These are key structures in order to prevent loss of genetic information and DNA damage activation at the chromosome termini, thus avoiding genomic instability, which can potentiate tumorigenesis. When a telomere became dysfunctional, for example by loss of telomeric proteins or due to telomere shortening, the DNA damage machinery is activated and the chromosome ends are processed as DNA breaks. This leads to checkpoint activation and repair through chromosome end-joining. Although many have studied how telomere fusions arise in the absence of key telomeric components, the formation of spontaneous end-to-end fusions is still poorly understood. Here we propose to dissect how spontaneous telomere fusions arise. For that we will use as model organism Schizosaccharomyces pombe, which telomeres have great similarities with the mammalian ones. Using a state-of-the-art plasmid assay we will conduct a transposon-based genetic screen in order to unravel new proteins required for the formation of telomeric fusions in a wild-type and unperturbed system. We will then focus on the clearest candidates from the screen and determine their role in telomere biology. Moreover, and in order to further understand how spontaneous telomeric fusions arise, we also aim to investigate the role of telomeric replication in this process. The fact the telomeres are long stretches of repetitive DNA sequences and also due to the formation of secondary structures, replication can be a challenging event, potentiating loss of telomere integrity.
Altogether, we foresee that this project will make a key contribution to our understanding of telomere dysfunction. Importantly, studying how spontaneous fusions arise and finding new components required for end-joining will also give new insights on how a normal cell can become tumorigenic.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/chromosome
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

FUNDACAO CALOUSTE GULBENKIAN
Address
Avenida Berna 45
1000 Lisboa
Portugal
Activity type
Research Organisations
EU contribution
€ 196 510
Administrative Contact
Jose-Mario Leite (Mr.)