ICL CHROM · DNA interstrand crosslink repair and chromatin remodelling

DNA interstrand crosslink repair and chromatin remodelling

Human cells are continuously exposed to insults that damage our DNA. DNA damage can come into many different flavours, from mutations in the sequence of DNA, to DNA cross-links that glue together two DNA strands, to breaks into the DNA molecule. To fix DNA damage, our cells are equipped with several mechanisms that identify the damaged DNA and repair it. Malfunctions in the DNA repair pathways, as in the case of human diseases such as Fanconi anemia, Bloom syndrome and Ataxia Telangectasia, results in increased cancer susceptibility and neurodevelopmental disorders. Understanding how DNA repair pathways are regulated and which proteins contribute to DNA stability is therefore essential for human health. In our cells, DNA is organized into a structure called chromatin, where the DNA molecule is wrapped around proteins called histones. Chromatin provides stability and compaction to DNA, allowing the approximately two meters of DNA of each human cells to fit into the cell nucleus. Chromatin is a very plastic and complex structure, and is roughly divided into ‘active’ compartments and ‘silenced’ compartments, which regulate the expression of genes that make up the different cell types of our body. A wide range of proteins are required to assemble, maintain and regulate chromatin, such as chromatin remodelling enzymes, histone chaperones and histone modifying enzymes. Chromatin can however also act as a barrier to proteins that want to access and bind DNA, including DNA repair proteins. Therefore, when a DNA lesion occurs, the chromatin structure has to be relaxed so that DNA repair enzymes can access the lesion and repair it. A number of chromatin remodelling enzymes, histone chaperones and modifiers have been found to function during DNA repair. This list is though likely far from being complete and there are some types of DNA repair, such as the repair of DNA inter-strand crosslinks, whose interplay with chromatin is still quite unclear. In this proposal, we aimed at identifying all the chromatin remodelling enzymes and histone chaperones that are recruited to DNA damage sites, and to characterize how they function together with DNA repair pathways. This will provide a better understanding of how DNA repair is enacted in a complex chromatin environment.

Data: CORDIS, © European Union