"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. 

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 .

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 .

Seminar talk by Dr. Nuria Ferrándiz from CIC - Centro de Investigación del Cáncer, 
Campus Miguel de Unamuno, Salamanca, Spain

title: tba

Most solid tumours are aneuploid, with higher rates of chromosome instability (CIN), making the understanding of the mechanisms of chromosome missegregation a crucial goal in cancer cell biology. Furthermore, mitotic errors can also lead to the formation of micronuclei (MN), which are susceptible to nuclear envelope rupture and can result in extensive genomic rearrangements, such as those commonly observed in chromothripsis. While the spindle mechanics that ensure proper genome segregation during cell division have been extensively studied, less attention has been given to other structures within mitotic cells, such as intracellular membranes and organelles, collectively known as endomembranes, including the nuclear envelope (NE) and Golgi remnants, endoplasmic reticulum (ER), and vesicles. Recent studies from our lab and others have shown that endomembranes, particularly the ER, can impair chromosome dynamics and promote aneuploidy and MN formation.

In our laboratory, our primary aim is to develop a comprehensive understanding of NE organization, remodelling, and reassembly during cell division, with a specific emphasis on the recruitment of NE proteins to chromatin during mitotic exit. To address these research aims, we have outlined specific goals, including:

• Investigating nuclear envelope morphology during early mitosis.
• Characterizing the molecular composition of nuclear envelope precursor structures.
• Studying the dynamics of individual NE precursor structures throughout cell division.
• Determining the impact of inhibiting the delivery of specific inner nuclear membrane (INM) components on NE reformation.

To achieve these objectives, we employ a multidisciplinary approach encompassing molecular biology, genome editing, biochemistry, and advanced imaging techniques to decipher organelle dynamics in mammalian cells.

DNA Repair Meeting 2026

on Physiological Causes and Consequences of Genome Instability

September 07 - 09 | Cologne, Germany

Registration Deadline: May 31st 2026

Registration portal !!!

Fritz Thyssen Forum

co-hosted by CECAD Research Center

speaker: Prof. Dr. Jan Karlseder (San Diego)

September 09 2026

Fritz Thyssen Forum

Cologne, Germany

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. 

Seminar talk by Prof. Jan Vijg from Albert Einstein College of Medicine, New York.

title: tba

Genome Instability in Aging and Disease

Genome instability, i.e., the tendency of the genome to acquire mutations and epimutations, underlies human genetic disease, causally contributes to cancer and has also been implicated in aging and age-related, degenerative conditions other than cancer. Little is known about the mechanisms that give rise to spontaneous changes in the genome or epigenome and how this may lead, in somatic cells, to increased cancer risk and loss of organ and tissue function with age. We study genome and epigenome instability as a function of age in various model organisms, including mouse and fruit fly, and its consequences in terms of alterations in tissue-specific patterns of gene regulation.

In the past we developed transgenic reporter systems in mouse and fruit fly, which allowed us to determine tissue-specific frequencies of various forms of genome instability, e.g., point mutations, deletions, translocations. By crossing the mutational reporter animals with mutants harboring specific defects in various genome maintenance pathways, the relevance of these pathways for the accumulation of specific forms of genome instability is assessed, in relation to the pathophysiology of aging. Similarly, by using knockdown approaches we assess the effect of specific genes implicated in longevity and healthy aging, e.g., SOD, FOXO, SIR2, on genome integrity.

We are currently focused on single-cell genomics to assess mutation frequencies and spectra in human tissues during aging. To gain insight into the possible functional consequences of random somatic mutations we use single-cell multiomics assays to link specific mutations to transcriptional and translational end point. 

MECHANISM AND CONSEQUENCES OF SLX4IP- AND ERCC1-XPF-DEPENDENT TELOMERE DYSFUNCTION (project 6)

lab: Stephanie Panier

Somatic cells have finite replicative lifespans because telomeres undergo progressive shortening after DNA replication, which can lead to genome instability and induce senescence. Telomere dysfunction has profound physiological consequences and promotes the accelerated development of many age-associated pathologies such as tumorigenesis and kidney disease. We have previously described the adapter protein SLX4IP as an important regulator of recombination-based Alternative Lengthening of Telomeres (ALT), which is a telomerase-independent telomere maintenance mechanism. Intriguingly, SLX4IP interacts with the heterodimeric structure-specific endonuclease ERCC1-XPF, which cleaves the 3′ flaps of DNA intermediates that occur during several DNA repair pathways and also as a consequence of telomere maintenance. The physiological importance of ERCC1-XPF is underscored by the fact that inactivating mutations in XPF are associated with several genome instability syndromes. In addition, ERCC1-XPF is essential for kidney homeostasis and its loss leads to glomerular aging and renal fibrosis. To date, it remains entirely unclear why and how SLX4IP interacts with ERCC1-XPF and how this interaction relates to the cellular and physiological functions of this endonuclease. The objectives of this research proposal are, thus, to understand how SLX4IP regulates ERCC1-XPF function to ensure telomere stability and to elucidate the physiological consequences of a dysfunctional SLX4IP-ERCC1-XPF module. Specifically, we propose to characterize the molecular relationship of SLX4IP and ERCC1-XPF, to investigate how SLX4IP modulates ERCC1-XPF telomere functions, and to understand the consequences of a dysfunctional SLX4IP-ERCC1-XPF module on general genome maintenance and on organ homeostasis using mouse kidney fibrosis as model system.