Maintaining genome integrity is essential in all organisms for normal cellular function and accurate propagation of the genome. It relies on elaborate multifactorial DNA repair machineries, which need to be coordinated with genome surveillance and cell cycle control mechanisms. Investigating how the cell precisely implements and orchestrates these repair mechanisms with other fundamental cellular processes is paramount to understanding how tumorigenesis is suppressed. 

Structure-specific DNA endonucleases (SSEs) are key players in the maintenance of genome integrity. They act as specialized surgical tools for the processing of a wide array of secondary DNA structures generated during DNA replication, repair and recombination processes as well as during transcription.

However, cleaving DNA bears its own risks for the cell, opening windows of opportunity for the occurrence of potentially dangerous chromosome alterations and rearrangements at the origin of cancer development. The action of structure-specific endonucleases must therefore be tightly coordinated with downstream events that will ensure that the integrity of the chromosome is fully restored. It is also pivotal for the cell to avoid any anarchic action of SSEs.

Our team has had a long-standing interest in dissecting the molecular mechanisms that ensure the spatio-temporal control of structure-specific endonucleases. 

Using the yeast Schizosaccharomyces pombe as a model organism, we have identified several pathways controlling the Mus81-Eme1 endonuclease in response to DNA damage and during the cell cycle. These control mechanisms proved to be remarkably elaborate, involving functional interactions between protein phosphorylation and sumoylation. 

Our team has also pioneered and remained at the forefront of studies on the human SLX4 tumour suppressor, the study of which now constitutes the core of our activity.  We and others demonstrated that SLX4 acts as a scaffold that controls and coordinates the XPF-ERCC1, MUS81-EME1 and SLX1 DNA repair and recombination nucleases. Importantly, SLX4 also serves as a scaffold for a number of other factors with key functions in genome maintenance and cell cycle control (Figure 1). Its importance for genome integrity is underlined by the fact that bi-allelic mutations in SLX4 (FANCP) can cause Fanconi anemia, a syndrome associating bone marrow failure with a predisposition to cancer. A fundamental role as a tumor suppressor is also confirmed by the cancer-prone phenotype of mice lacking functional Slx4, and by a growing number of cancer-associated mutations in human SLX4.

We are combining biochemical and structural studies with cell biology, proteomics and genomics in both fundamental and translational research projects to to better understand the multiple functions of SLX4 in maintaining genome integrity and their relevance to cancer biology.