Project description
Understanding rDNA damage in senescence for tumour therapies
Ribosomal DNA (rDNA) is vital for protein synthesis. In senescent cells, rDNA damage causes genomic instability and activates pathways associated with the senescence-associated secretory phenotype (SASP), which may promote tumour growth and therapy resistance. Still, the causes remain unclear. Supported by the Marie Skłodowska-Curie Actions programme, the NuSEN project will investigate how changes in the nucleolus during senescence affect the rDNA damage response and rDNA stability. Using an oncogene-induced model, the project will analyse the impact of structural alterations and increased rRNA transcription, linking rDNA damage to SASP activation. The findings are expected to enhance our understanding of genome instability in senescence and identify potential biomarkers and therapies to address cancer associated with senescent cells.
Objective
Ribosomal DNA (rDNA) encodes the ribosomal RNAs essential for protein synthesis and thus for cell growth and maintenance. Owing to its repetitive nature, high GC content, and intense transcriptional activity, rDNA is among the most fragile genomic regions and is normally safeguarded by a specialized nucleolar DNA damage response (n-DDR). In senescent cells, however, persistent rDNA damage accumulates, coinciding with genomic instability and the chronic activation of inflammatory signaling pathways that drive the senescence-associated secretory phenotype (SASP). SASP has strong tumour-promoting effects and contributes to malignancy and therapy resistance. Despite these observations, the causes of persistent rDNA damage in senescence and its connection to genome instability and SASP remain poorly understood.
This project will address this critical gap by investigating whether the profound remodeling of the nucleolus during senescence, including structural reorganization and rRNA hyper-transcription, impairs the fidelity of n-DDR and compromises rDNA stability. Using an oncogene-induced senescence model, I will pursue three objectives: (1) test how nucleolar reorganization and elevated rRNA transcription affect n-DDR fidelity using advanced imaging and quantitative proteomics, (2) identify structural alterations and mutational signatures that accumulate at rDNA loci through long-read sequencing and computational analysis, and (3) establish the causal link between rDNA damage and SASP activation by applying genomic approaches and targeted perturbations.
This project will deliver the first mechanistic framework for nucleolar genome instability in senescence. Beyond advancing our understanding of genome maintenance, it may reveal novel biomarkers of senescence and uncover therapeutic opportunities to reprogram or suppress the pro-cancerous activities of senescent cells, thereby contributing to strategies that reduce cancer burden.
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
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics RNA
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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2100 Koebenhavn
Denmark
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