Project description
Novel repair mechanisms to improve cancer treatment
Etoposide is a chemotherapeutic drug used in treating various cancers. It operates by halting the TOP2 catalytic cycle and producing toxic DNA lesions known as TOP2-DNA-protein crosslinks (TOP2-DPCs). While enzymes that counteract these lesions have been identified, the protein ZATT is a recent discovery that promotes TOP2-DPC resolution. However, the coordination of different repair modes by ZATT via TOP2-SUMOylation remains unclear. In this context, the ERC-funded TOPO2_REPAIR project will employ a novel approach using Xenopus egg extracts to investigate TOP2-DPC repair, offering a unique opportunity to comprehend the molecular mechanisms involved in this process. Its aim is to elucidate the mechanisms for counteracting TOP2 lesions and uncover the molecular triggers that activate various repair pathways to enhance cancer treatment.
Objective
Topoisomerase II (TOP2) chemotherapeutics such as etoposide have been widely used in the clinic to treat leukemias, lymphomas, lung, testicular, and ovarian cancers. Etoposide was first approved for clinical usage in 1983. By intercalating into DNA, etoposide stalls the TOP2 catalytic cycle, generating toxic DNA lesions known as TOP2-DNA-protein crosslinks (TOP2-DPCs). After 40 years of intense research, the mechanisms employed by cells that counteract these lesions are starting to emerge. These include enzymes that reverse the crosslink, degrade the protein adduct, or remove the lesion by DNA incisions. Moreover, the protein ZATT was recently described as an essential regulatory enzyme that SUMOylates TOP2 and thereby stimulates TOP2-DPC resolution.
Important and long-standing questions in the field relate to our understanding of how the different modes of repair are activated, coordinated between one another, and preferentially used by cells. Based on genetic data, ZATT appears to be the primary responder to TOP2-DPCs but how ZATT coordinates the different modes of repair via TOP2-SUMOylation is currently unclear.
To address these questions and study TOP2-DPC repair, we propose to use a novel approach based on Xenopus egg extracts, which can recapitulate DNA repair mechanisms in a soluble environment. As part of our preliminary data, we show that these extracts can recapitulate TOP2-DPC repair via ZATT SUMOylation, providing a unique opportunity to delineate the molecular mechanisms underlying this reaction. By combining this system with complementary and innovative approaches, we seek to obtain a clear molecular understanding of the different mechanisms counteracting TOP2 lesions and unravel the molecular triggers that activate the different routes of repair. By doing this, we will provide new opportunities and targets to improve cancer 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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
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Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
1165 Kobenhavn
Denmark