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.
Today’s major challenge lies in understanding 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.
Elucidating the molecular mechanisms that modulate the activities of genome maintenance pathways in the cell will be the central goal of the SFB 1361.
The consortium will approach this goal on three interconnected levels, encompassing
(1) the origins of genome instability,
(2) the perception of genotoxic stress (damage sensing) and
(3) the systems for its resolution (DNA repair).
This interdisciplinary network brings together experts in structural biology, organic chemistry, biochemistry, molecular and cell biology 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 since 2019 with its second funding period running from January 2023 until December 2026.