DNA Repair State Machines

Informations projet

RepState

N° de convention de subvention: 101073485

DOI

10.3030/101073485

Date de signature de la CE 18 Juillet 2022

Date de début 1 Février 2023

Date de fin 31 Janvier 2027

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 2 764 144,80

Coordonné par

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands

Periodic Reporting for period 1 - RepState (DNA Repair State Machines)

Période du rapport: 2023-02-01 au 2025-01-31

Résumé du contexte et des objectifs généraux du projet

The RepState project (http://www.repstate.eu) creates a Doctoral Training Network focused on advancing our understanding of the molecular mechanisms behind DNA Repair State Machines, which are crucial for maintaining genome stability. The project addresses significant challenges in the field of DNA repair related to the Mismatch Repair, Nucleotide Excision Repair (NER), and Transcription-Coupled NER pathways. Understanding how these state machines operate has profound implications for genome maintenance, cancer treatment, and overall human health.
RepState involves 11 participants from academia, industry, and the creative sector. The consortium includes experts from natural and social sciences, creating a unique interdisciplinary environment. Renowned research organizations and universities provide an excellent setting for innovation. This collaboration supports a multidisciplinary PhD program for 13 Doctoral Candidates(DCs), offering advanced training in the fundamental chemical and physical principles underlying biology and human health.
The training program combines local academic activities, lab rotations, non-academic sector exposure, and annual meetings. Fellows receive advanced scientific training along with courses in transferable skills and career development. A key feature is the focus on communication and dissemination, where fellows collaborate with the creative sector to present their research through innovative formats like scientific animations.
RepState's research objectives focus on developing new technologies with high temporal and spatial resolution to study the structure and function of DNA Repair State Machines. The project not only aims to advance fundamental scientific knowledge but also to produce a new generation of innovative scientists with expertise in technology development, career opportunities in multiple sectors, and a deep understanding of the societal importance of fundamental science. By combining academic excellence, interdisciplinary collaboration, and communication through creative channels, RepState aims to make a significant impact on both science and society.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Since the start of the RepState project, we have made significant progress in both the scientific and organizational aspects of the project. We have:
-successfully recruited 13 talented DCs, who are now actively engaged in their research projects across the consortium.
-organized three face-to-face meetings, facilitating collaboration and knowledge exchange among project partners, young researchers, and external experts.
-organized three scientific workshops, two of which were preceded by pre-online modules to prepare the DCs with foundational knowledge. These workshops have focused on advanced methodologies and concepts related to DNA repair state machines, equipping the researchers with both theoretical and practical skills.
-organized the secondments. 9 secondments are now completed, with the students gaining valuable experience and expanding their networks by working in different academic settings.
These achievements demonstrate that the project is on track, with important milestones reached in both training and research activities.
-We created MMR and TC-NER protein variants with mutations in their ATPase site and heterodimeric and crosslinked variants. We are analysing these variants using biochemical, structural and single molecule approaches including DNA and protein binding assays, R-loop formation, cryoEM, mass spectrometry, FRET incision and excision assays and in vivo imaging.
These activities reflect strong progress in understanding the molecular mechanisms of DNA repair while addressing challenges through adaptations to ensure project success.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The RepState project aims to push the boundaries of DNA repair research by developing cutting-edge technologies with high temporal and spatial resolution, providing new insights into the structure and function of DNA Repair State Machines involved in key repair pathways. These advancements will improve our understanding of how genome stability is maintained and open new avenues for therapeutic applications, particularly in cancer treatment.
Key expected results include:
- Development of novel molecular tools and techniques for visualizing and manipulating DNA repair mechanisms in real-time.
- Discovery of new mechanisms of lesion recognition, DNA incision, and unwinding, which could lead to breakthroughs in DNA repair efficiency.
- Understanding the coordinated activity of multiple DNA repair state machines, enabling a more comprehensive view of how cells respond to genetic damage.
These results are expected to have a wide-ranging impact, from advancing fundamental molecular biology to enabling more effective therapeutic interventions for genome instability-related diseases. The collaboration with WDKA (Willem de Koning Academy) in the development of scientific animations plays a unique role in this project. This collaboration enhances the project’s dissemination efforts and helps translate complex scientific concepts into engaging, understandable formats.

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