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Dna Repair Within Centromeric Heterochromatin

Reference : PhD Evi SOUTOGLOU

Offer publication : April 6, 2016

Cells continuously experience stress and damage from exogenous sources, such as UV light or irradiation, and endogenous sources, such as oxidative by-products of cellular metabolism that endanger genome stability. Several pathways have evolved to detect DNA damage, signal its presence and mediate its repair. Double Strand Breaks (DSBs) are the most harmful DNA breaks because their unfaithful repair can lead to
chromosomal translocations and cancer. Cells respond to DSBs by initiating a signaling cascade called DNA damage response (DDR) that activates cell cycle checkpoints and promotes repair of the broken ends. Although, there has been much progress in identifying key factors of DDR and DNA repair, only recent cell-biological approaches have started to reveal how they function in the context of local high-ordered chromatin structure and nuclear space.

Repairing DSBs arising within highly compacted structures like heterochromatin, represents a challenge that cells need to overcome to preserve genome integrity. This proceeds through rapid changes in chromatin condensation. Nevertheless, little is known about the underlying mechanisms, the protein complexes involved, the choice of DNA repair pathways or the kinetics of DNA repair. Moreover, although the ATM kinase plays a key role in the repair of DSBs, it is not clear whether the recruitment of ATM to heterochromatin is preceded by chromatin remodeling activities. It is also not known whether alternative mechanisms contribute (and to what extent) to the repair of heterochromatic breaks. Furthermore, although global DNA damage results in heterochromatin expansion and re-localization of breaks outside of the domain, the kinetics of these events and their
interdependency has not been explored.

To address these questions we have developed an innovative cellular system which allows us to fluorescently label different heterochromatin structure in living cells and to robustly and homogeneously induce DSBs exclusively within heterochromatin. Using this system we aim to study the repair pathways induced in heterochromatin and identify novel factors that are essential in repair heterochromatic lesions.

We will employ advanced confocal and superresolution microscopy techniques to study the DNA repair pathways that are activated in different types of heterochromatin. We will also utilize quantitative proteomic methods to identify novel proteins that are involved in repair of lesions occurring in heterochromatin.

- WISHED SKILLS : Basic molecular biology and cell culture experience

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : CRISP/Cas9 technology, Microscopy, superresolution microscopy, biochemistry, molecular biology.

Your application

Application Deadline : Dec. 31, 2016

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