Project description
Elucidating the dynamic repair responses to DNA damage in heterochromatin
Chromosomes have two structurally and functionally different domains: euchromatin and heterochromatin. The former contains most of the organism’s genes and is less condensed, while the latter is highly condensed, contains few genes and many repetitive DNA sequences, and is transcriptionally silent. It plays an important role in maintaining genome stability. The DNA repair mechanisms of heterochromatin are poorly understood. The ERC-funded HETREPAIR project aims to elucidate the responses to DNA damage in heterochromatin domains and determine their role in maintaining genome stability and tissue health. This will be done using in vitro and in vivo model systems of heterochromatin damage and repair, proteomics, single-cell chromatin analyses, and live imaging.
Objective
Cells face continuous challenges from insults that damage their DNA. To safeguard DNA integrity, a range of repair mechanisms have evolved, which are crucial for organismal survival. However, the eukaryotic nucleus contains different chromatin domains, each requiring specific repair mechanisms to ensure genome stability. In particular, the compact and transcriptionally silenced heterochromatin domains, which are riddled with repetitive DNA and developmental genes, are a challenging environment to repair DNA damage.
Despite covering a substantial amount of our genome and being essential for organismal viability and development, heterochromatin remains poorly understood in its response to DNA damage. Heterochromatin domains possess specific molecular and biophysical properties, which I hypothesize necessitate unique chromatin responses at the damaged site to ensure effective repair and maintain genome stability.
The aim of this proposal is to identify the dynamic responses to DNA damage in heterochromatin domains and determine their role in maintaining genome stability and tissue health. I will study this across scales, utilizing our recently developed in vitro reconstitution systems that mimic DNA damage in heterochromatin, as well as our unique in vivo systems to study and manipulate heterochromatin repair in fruit fly tissue. These approaches will be integrated with state-of-the-art proteomics, single-cell chromatin analyses and live imaging to identify the mechanisms of DNA repair in heterochromatin, and ultimately determine their impact on genome maintenance and tissue homeostasis.
Unravelling chromatin dynamics during DNA repair in heterochromatin has the potential to yield broader insights into their role in other essential nuclear processes such as DNA -replication and -transcription. Importantly, HETREPAIR could in the long-term shed light on how heterochromatin repair processes are disrupted in disease and how these can be exploited during treatment.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics DNA
- agricultural sciences agriculture, forestry, and fisheries agriculture horticulture fruit growing
- natural sciences biological sciences genetics genomes
- medical and health sciences basic medicine physiology homeostasis
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-COG
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3584 CX Utrecht
Netherlands
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