PHYSIOLOGICAL CAUSES AND CONSEQUENCES OF GENOME INSTABILITY

guest: Prof. Jörg Kobarg (University of Campinas)

Cancer is among the diseases that most kill humans and domestic animals. Depending on the tissue and cell type affected by mutations, a large number of sub-types of cancer can be differentiated. For a specific sub-type of cancer the molecular causes can be quite heterogeneous and for the majority of cases are poorly mapped. This represents both a major challenge as well as an opportunity in the field, since an intense study of the molecular causes can lead to new diagnostic and therapeutic strategies. Protein kinases in signaling pathways and regulatory proteins in general, are frequently affected by activating or inactivating mutations in cancer and therefore contribute to cancer transformation. We study two families of proteins with great potential of utility for both diagnostic and therapy in cancer. For the Nek family of serine/threonine protein kinases we focus on: Nek1,4,5,6,8, and 10, which are involved in the regulation of the cell cycle, mitosis, primary cilia function, DNA repair mechanisms and mitochondrial functions. The second family comprises the two human regulatory proteins, called HABP4 and SERBP1, that have roles in the regulation of transcription and gene expression, cell proliferation and the cell's responses to stress. Gene knock out studies and functional cellular and biochemical assays showed a new functional axis for the Nek kinases in the regulation of mitochondrial morphology and respiration. In case of the HABP1/SERBP1 regulatory proteins, molecular biology studies over the years point to a role in the regulation of mRNA stability or turn over. Novel data highlight the potential of both protein families for improved cancer diagnostics/prognostics, and in case of the Nek family members, also as potential novel target proteins for small molecular inhibitors, in cancer.   

While humans and house mice develop kidney failure upon injury, the spiny mouse has a unique mechanism to repair kidney injury and prevent concomitant permanent kidney failure. My aim is to decipher the unique regenerative capacity by identifying the master switches which are repressed in humans and house mice by using tubuloids of spiny mice. The master switches can be targets in future regenerative medicine applications.

We aim to explore the causes and consequences of deregulated DNA repair to explain important phenotypes observed in our novel human genome instability syndromes. Importantly, these insights will serve as a blueprint to understand the intricate relationship between the DDR, protein homeostasis and neurodegeneration. 

Environmental Stress and Chromatin Dynamics: Investigating Epigenetic Responses in C. elegans

Dr. Daphne Selvaggia Cabianca's research at the Helmholtz Institute Munich focuses on how environmental factors influence chromatin organization and function. Using *C. elegans* as a model organism, her group explores how changes in diet, temperature, and other external stimuli impact the spatial architecture of chromatin and gene expression. A key area of her work is understanding how chromatin modifications can contribute to "stress memory," enabling organisms to respond more effectively to future stress. Her lab employs advanced techniques such as CRISPR-Cas9, RNAi screens, and live-cell microscopy to investigate how metabolic changes affect chromatin states and their broader effects on organismal health.

Telomere Biology and Cancer: Unraveling the Role of Chromatin and DNA Repair in Genome Stability

Seminar talk in cooperation with the Cologne Graduate School of Ageing Research (CGA).

Dr. Roderick O'Sullivan's research at UPMC Pittsburgh focuses on understanding how telomeres, the protective caps at the ends of chromosomes, maintain genome stability. His lab investigates the proteins that regulate telomere structure and function, particularly within the Alternative Lengthening of Telomeres (ALT) pathway, which is implicated in certain cancers. By studying chromatin dynamics and DNA repair mechanisms at telomeres, O'Sullivan aims to uncover how telomere dysfunction can lead to genomic instability, a hallmark of cancer. His research also explores how modifications like poly-ADP-ribosylation impact telomere maintenance and cellular aging.

Sara and Anja are investigating how mechanical stress leads to DNA damage and affects genome mechanoprotection in cellular and organismal homeostasis. Their work focuses on uncovering the mechanisms through which physical forces trigger chromatin changes, replication stress, and DNA damage. This project aims to enhance our understanding of the role of mechanical stress in genome stability and its broader implications for tissue functionality.

A damage driven transcription stress on aging and the effect of calorie restriction, project 7

Joris investigates how chronic genome instability disrupts tissue homeostasis, focusing on transcriptional stress and its systemic impacts during aging. Using progeroid DNA-repair-deficient mouse models, he revealed that transcriptional stalling induces metabolic dysfunction and accelerates tissue degeneration, including neurodegeneration. His groundbreaking discovery of dietary restriction as a therapy shows it mitigates DNA damage, reprograms metabolism, and significantly extends lifespan, offering a translational approach to aging-related diseases.

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.