rDNAstress · Novel insights into DNA damage and stress responses in the nucleolus: Mechanisms and relevance for genomic (in)stability and cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-01-01 → 2020-12-31
- EU contribution
- €212,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Novel insights into DNA damage and stress responses in the nucleolus: Mechanisms and relevance for genomic (in)stability and cancer
The Action "rDNAstress" contributes to target one of the priority challenges defined by the European Union: Health, demographic changes and well-being. The main objective of this challenge is health-improving during life and increasing the welfare of society. Importantly, the proposed project is generating in-depth knowledge about genome instability in human cells to understand cancer disease. Hopefully, this project's results will help extend our knowledge about a minimal region of the human genome, named ribosomal DNA, which is essential to genome maintenance and could be a potential tool for targeting cancer cells. Furthermore, the functional role of the ribosomal DNA to synthesize ribosomes, main machinery for protein synthesis, which is overstimulated in cancer cells, makes this proposal attractive to improve and develop new approaches and strategies for cancer treatments. Indeed, the proposal has developed and improved new methods and innovative technologies to uncover new factors involved in genome stability allow us to improve in the diagnosis and prognosis, opening the possibility of more personalized medicine. The overall objective of this action has been to assess rDNA damage and the ensuing genomic instability in human cells exposed to insults such as radiation, chemotherapy drugs, replication and transcription stress, ribosome biogenesis stress, and oncogenes, identify and functionally characterize signalling and repair factors that guard nucleolar integrity and function, and investigate how tumour cells may evade such control of nucleolar (replication) stress. To achieve these goals, we have employed innovative cellular models, molecular genetic, cell biology, and imaging technologies and functional assays. The expected results are providing novel insights into genome integrity maintenance and cellular stress responses and may inspire the design of future strategies to treat or even prevent cancer. Unfortunately, during this active period, the current COVID-10 pandemia has impacted our society, our lives and also in our project execution due to the continuous outbreak in Denmark and strict restrictions in the research centre environment. To solve this situation, we have depth in some previous results obtained before COVID-19 outbreak, and we get promising results that they will publish soon, hopefully.
Data: CORDIS, © European Union
Project objective
Incidence of grave pathologies including neurodegeneration and cancer increases in today’s aging European populations and new approaches to battle these diseases are required. Shared by these pathologies and premature aging syndromes is the enhanced DNA damage and genomic instability, likely causal phenomena that can be better understood by functional elucidation of the cellular DNA damage response (DDR) machinery and its defects. The central hypothesis of this project is that ‘nucleolar genome’ that contains many copies of rDNA genes, the repetitive and most highly transcribed genomic sequences essential for ribosome biogenesis and protein synthesis, may represent an exceptionally vulnerable ‘Achilles heel’ of our genome whose instability fuels aging and tumorigenesis. This project proposes to approach this problem by a combination of innovative cellular models and techniques including gene editing, proteomics and live cell imaging, to assess rDNA damage and the ensuing genomic instability in human cells exposed to exogenous (radiation, chemotherapy drugs) and endogenous (replication and transcription stress, ribosome biogenesis stress, activated oncogenes) insults and identify and functionally characterize signalling and ‘repair’ factors that guard nucleolar integrity and function. This proposal is timely due to the emerging concept of nucleolus as a sensor of diverse stresses and the fact that technological advances now allow analysis of the difficult-to-assess rDNA genes. The applicant is experienced in the DDR field and modern technologies, the receiving institute is among the world leading centers in DNA damage, cancer and cell stress research fields. These aspects, together with the large body of preliminary unpublished data makes this ambitious project feasible. The results will provide novel insights into genome integrity maintenance and cell stress responses, and may inspire novel strategies to treat or even prevent age-related diseases, especially cancer.
Original text from CORDIS.
Participants
- KRAEFTENS BEKAEMPELSE · KoebenhavnCoordinatorDenmark
Links
Data: CORDIS, © European Union