PHYSIOLOGICAL CAUSES AND CONSEQUENCES OF GENOME INSTABILITY

DNA Damage Tolerance: Physiological and Cancer Therapeutic Relevance

Seminar talk by Dr. Heinz Jacobs from Netherlands Cancer Institute Antoni Van Leeuwenhoek.

DNA Damage Tolerance is Essential for Hematopoietic Stem Cell Maintenance and Mammalian Life
Stem cells are key players in central biological processes, such as tissue homeostasis, ageing, and cancer formation. Stem cell depend on genome maintenance to prevent disease formation. DNA damage tolerance (DDT) pathways enable DNA replication in the presence of replication impediments and are regulated by PCNAK164 ubiquitination and REV1. The failure to generate PcnaK164R/K164R;Rev1-/- deficient mice revealed DDT as essential for mammalian life. The compound mutation rendered hematopoietic stem cells (HSCs) and the hematopoietic precursors genetically unstable, instigating a pathological process where the associated HSC depletion culminated in a severe, embryonic-lethal anemia. Single cell RNA-sequencing of the remaining HSCs and progenitors identified CD24Ahigh and CD93low erythroid-biased progenitors (EBP) within the Lineage-, Sca1+, cKit- (LSK) population. In line, this subset was found to depend on the erythroid transcription factor Klf1. In conclusion, DDT is an essential activity within the DNA damage response network and in maintaining HSC fitness. By studying this system, we identified an erythroid-biased progenitor subset within the LSK compartment.

"Metabolic deregulation, genome instability, and the progression of chronic kidney disease", (project 8)

Our data suggest that the accumulation of unresolved DNA damage is linked to metabolic changes that may, in a vicious cycle, drive further genome instability, chronic kindey disease (CKD) progression, and kidney fibrosis. This project is expected to further substantiate this link and present potential strategies for future tissue-protective strategies with the ultimate long-term goal to confirm these findings in samples from patients and to develop strategies for future clinical applications. 

"Epigenetic determinants of genome stability for mammalian tissue", (project 1)

This project will elucidate epigenetic mechanisms promoting genome instability when tissue homeostasis declines with age and under physiological stress. We discovered elevated G– quadruplex (G4) DNA secondary structure formation in mutated highly transcribed gene regulatory regions of cancer, suggesting dysregulated G4s as promoter of genome instability. We have and continue to gather evidence that dysregulated G4s emerge before cancer development in physiologically aged murine tissues and rapidly aged murine and human models. We hypothesize here that dysregulated G4 secondary structure formation may promote genome instability and heterostasis in aged and stress-induced rodent tissues. By exploiting our newly developed multiomics technology to jointly map epigenetically linked DNA breakage landscapes, beyond association, we will identify epigenetic mechanisms that critically drive persistent and/or elevated DNA breakage. To identify epigenetic regulators that promote an increase in epigenetically linked DNA breakage in tissues of our rodent models, we will use computational predictions and experimental associations of our multiomics data with existing data sets. We will use proximity ligation proteomics of tissue-derived nuclei to directly link regulatory factors to epigenetically linked DNA breakage and validate these findings by genetic loss-of-function in C. elegans. 

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Seminar talk by Dr. Martijn S. Luijsterburg from Leiden University Medical Center.

Dr. Martijn S. Luijsterburg (Leiden University Medical Center) will present recent work on the molecular mechanisms underlying transcription-coupled DNA repair. His research combines genetic, genomic, and proteomic approaches to study how cells recognize and process DNA damage that interferes with transcription. The seminar will highlight new insights into the coordination between transcription, chromatin remodeling, and DNA repair pathways.

"Mechanical-stress induced DNA damage and genome mechanoprotection in cellular and organismal homeostasis", (project 2)

The nematode C. elegans is an excellent in vivo model system for DNA damage and repair responses. To understand the role of mechanical forces as physiological trigger of DNA damage in live animals, we will visualize and quantify relationships between nuclear deformation and DNA damage and analyze its functional consequences of organismal function, focusing on the highly dynamic C. elegans germline. 

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Seminar talk by Dr. Daphne S. Cabianca from Helmholtz Zentrum, Munich.

Dr. Daphne S. Cabianca leads the Environment and Nuclear Organization group at Helmholtz Munich’s Institute of Functional Epigenetics. Her research focuses on how environmental cues—such as temperature or nutrient availability—reshape chromatin organization and gene expression. Using C. elegans as a model, her team combines CRISPR-based genome engineering, live imaging, and sequencing approaches to uncover how spatial chromatin dynamics contribute to cellular adaptation.