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Studying DNA replication in eukaryotic cells presents additional layers of complexity as chromosomes are packaged in nucleosome arrays that protect and regulate the genome. Eukaryotic replication therefore entails three unique tasks : i. identifying DNA stretches accessible for MCM loading ii. disrupting the nucleosomes that form chromatin ahead of the replication machinery, and iii. repopulating chromatin on duplicated DNA. To perform these functions, the eukaryotic replisome interacts with histones through core or accessory components. My group is currently building new biochemical tools to study chromatin replication under the electron microscope.

Chromatin is the natural substrate of the eukaryotic replisome, which contains functional domains for chaperoning histones from the parental to the duplicated DNA at the replication fork. Flexible chaperone domains become structured when histone-engaged. Therefore, studying the full replisome assembled on chromatin can provide a more complete view of chromosome replication, explaining the mechanisms of nucleosome-roadblock bypass and histone reshuffling during replication fork progression.

Cryo-EM structure of a nucleosome.

Figure 1: Cryo-EM structure of a nucleosome.