PHYSIOLOGICAL CAUSES AND CONSEQUENCES OF GENOME INSTABILITY

Radiation biology and DNA repair

Prof. Dr. Markus Löbrich (TU Darmstadt)

Our laboratory investigates the repair of DNA double-strand breaks (DSBs), the most toxic lesions endangering cellular viability. We are interested in dissecting DSB repair mechanisms and uncovering novel repair factors, providing basis to understand the pathogenesis of diseases such as cancer and the development of novel radio- and chemo-therapeutic strategies.

MD Fellowship Project Presentations

Giuseppe Oppedisano and Lukas Koch were awarded the FOR5504 MD Fellowship in November 2023, receiving a one-year stipend to dedicate full-time efforts to their individual research projects.

• Giuseppe Oppedisano conducted his research in the workgroup of Dr. Miguel Angel Alejandre Alcázar (Department of Pediatric and Adolescent Medicine). His project, titled “Interplay of Early Life Obesity, Genome Stability, and the Risk for Cardiopulmonary Diseases through Adipocyte-Secreted Extracellular Vesicles (EVs),” investigates how obesity in early life may influence genome stability and elevate risks for cardiopulmonary conditions via signals transmitted by EVs from fat cells.

• Lukas Koch worked in the group of Prof. Dr. Carien M. Niessen at CECAD. His project, “The Role of Cell Polarity in Mitochondrial Dynamics and Cell Fate in Field Cancerization and Squamous Cell Carcinoma Formation,” explores how disruptions in cell polarity impact mitochondrial behavior and contribute to the development of cancerous fields and squamous cell carcinoma.

Coordination of DNA damage response and aging by ubiquitin signaling, project 4

The project focuses on understanding the role of ubiquitin signaling in genome stability during development and aging. The project investigates how the ubiquitin-proteasome system (UPS) is involved in the repair of DNA double-strand breaks (DSBs), which is crucial for maintaining genome integrity. The team aims to uncover the physiological impact of ubiquitin-dependent regulation on DSB repair and its connection to aging. By using Caenorhabditis elegans as a model, they will apply techniques such as CRISPR/Cas9, proteomics, and time-lapse microscopy to explore the tissue-specific effects and coordination of ubiquitin signaling in DNA repair. The ultimate goal is to shed light on how dysregulation of these processes contributes to age-related genome instability and disease .

Epigenetic Regulation of Cellular Homeostasis Amid Transcription-Blocking DNA Damage During Development and Aging, project 3

The research project focuses on how epigenetic mechanisms, particularly the deposition of H3K4me2 by the MLL/COMPASS complex, are regulated in response to transcription-blocking DNA damage. It investigates how this histone modification aids in the recovery of transcription elongation and the maintenance of cellular homeostasis during both development and aging. Using *C. elegans*, the study seeks to understand the physiological consequences of genome instability, particularly how impaired or enhanced deposition of H3K4me2 influences growth and longevity .

Radiation biology and DNA repair

Prof. Jörg Kobarg (University of Campinas)

His research group investigates the role of specific proteins in processes such as DNA damage repair, cellular stress response, and cancer development. One key aspect of his work involves studying protein-protein interactions and their implications for understanding how cells maintain genomic stability under stress conditions. Prof. Kobarg’s work has significant applications in cancer biology, as it aims to identify potential therapeutic targets by exploring the molecular mechanisms that drive tumor development and progression.

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.