DNA is the carrier of a cell’s genetic information. As such, it needs to be maintained for long-term storage, duplicated as the cell proliferates, and made accessible for read-out in order to support cellular metabolism. However, like all biological molecules, DNA is vulnerable to damage and decay, which necessitates a battery of defensive mechanisms to protect it against a multitude of threats.
Over the past decades, the major pathways of genome maintenance and their key players have been elucidated, providing insight into how various sources of genotoxic stress are detected by the cell and channelled into appropriate maintenance pathways. Yet, the origins of genome instability are extremely diverse and sometimes unforeseeable as they arise in a changing environment. Moreover, DNA lesions are often interconvertible by the cell’s own metabolism or defence pathways, and their biological effects depend on factors such as the cell type, the cell cycle stage or their location within the genome. As a consequence, the cellular response to genotoxic insults exhibits a corresponding flexibility, and a given insult can usually be processed by more than one particular pathway, with sometimes vastly different outcomes for the cell and the organism.
Within the SFB 1361, we aim to understand the regulatory mechanisms that control the choice between the individual pathways in the context of chromatin, the cell nucleus and the cell’s physiological state in general, their fidelity and their interdependencies in response to different insults.
During its first funding period (2019-2022), the SFB 1361 made ground-breaking advances in characterizing the components of DNA repair and DNA damage signalling pathways that act as decision-makers in the regulation of genome maintenance. Structural studies have provided insight into the mechanisms of DNA damage signalling at DNA double-strand breaks, and genomic approaches have revealed the origins of oncogenic chromosome aberrations resulting from such lesions. Overall, the research has highlighted the relevance of endogenous factors as sources of genome instability.
In its second four-year funding period (2023-2026), the SFB 1361 is deepening its mechanistic analysis of genome maintenance systems and intensifies its efforts to draw functional connections between individual repair pathways in order to integrate them into larger regulatory networks. This involves enhanced systems-level approaches to determine the genome-wide distribution of lesions. The researchers are focussing their investigation primarily on various endogenous sources of genome instability, how they are perceived by cellular signalling pathways and processed by dedicated or overlapping DNA repair pathways, and their implications for cell fate.
This interdisciplinary network brings together experts in structural biology, organic chemistry, biochemistry, molecular and cell biology, bioinformatics as well as genetic toxicology and clinical sciences from Mainz, Darmstadt, Frankfurt and Munich. It will make use of state-of-the-art tools in microscopy, proteomics, genomics, damage detection and quantification as well as a wide panel of DNA repair assays.
The SFB 1361 is funded by the DFG (Deutsche Forschungsgemeinschaft – German Research Foundation).