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Dissecting the chromatin response to DNA damage in silenced heterochromatin regions

Project description

Still waters may run deep when it comes to 'inactive' regions of chromatin

The genome of eukaryotic cells is tightly packed as chromatin (DNA associated with proteins). The chromatin exists in two different forms simultaneously. Heterochromatin is very dense and packed, limiting access to transcription factors. It has low gene density and late onset of DNA replication. Euchromatin is less condensed and is transcriptionally active. Until recently, researchers considered heterochromatin to be a 'genetic junkyard', yet it is now known to be critical to chromosomal stability throughout the cell cycle. The EU-funded CHROMREP project is investigating the DNA damage repair mechanisms of the different chromatin domains, with a focus on heterochromatin. New insights could point to ways in which mutations in heterochromatin impact genetic stability and play a role in tumour processes.


Cells are continuously exposed to insults that can break or chemically modify their DNA. To protect the DNA, cells have acquired an arsenal of repair mechanisms. Proper repair of DNA damage is essential for organismal viability and disease prevention. What is often overlooked is the fact that the eukaryotic nucleus contains many different chromatin domains that can each influence the dynamic response to DNA damage. Different chromatin environments are defined by specific molecular and biophysical properties, which could necessitate distinct chromatin responses to ensure safe DNA damage repair.
The aim of this proposal is to understand how diverse chromatin domains, and in particular the dense heterochromatin environment, shape the dynamic chromatin response to DNA damage.
I recently developed locus-specific DNA damage systems that allow for in-depth analysis of chromatin domain-specific repair responses in Drosophila tissue. I will employ these systems and develop new ones to directly observe heterochromatin-specific dynamics and repair responses. I will combine these systems and state-of-the art chromatin analysis with high-resolution live imaging to dissect the DNA damage-associated heterochromatin changes to determine their function in repair -kinetics, -dynamics and -pathway choice.
Deciphering the chromatin dynamics that regulate DNA damage repair in heterochromatin will have broad conceptual implications for understanding the role of these dynamics in other essential nuclear processes, such as replication and transcription. More importantly, understanding how chromatin proteins promote repair will be important in determining how cancer-associated mutations in these chromatin proteins impact genetic instability in tumours in the long run.

Host institution

Net EU contribution
€ 1 499 404,00
3584 CX Utrecht

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West-Nederland Utrecht Utrecht
Activity type
Higher or Secondary Education Establishments
Total cost
€ 1 499 404,00

Beneficiaries (1)