REPLISOMEBYPASS SIGNED

Project "REPLISOMEBYPASS" data sheet

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 Project objective

Faithful duplication and transmission of genetic and epigenetic information is the most vital cellular function for the preservation and proliferation of life. In cells, this process is conducted by large macromolecular complexes, known as replisomes, that coordinate the sequence of enzymatic events during chromosome duplication. While recently developed single-molecule techniques promise unprecedented access to the complex inner workings of these sophisticated machines, most studies conducted have focused on individual factors, operating on non-physiological substrates, which has provided an incomplete molecular picture. My recent development of a multidimensional, single-molecule imaging approach that allows for real-time visualisation of coordination during replication represents a significant breakthrough in our ability to study macromolecular machines in vitro. Building on this success, here I describe single-molecule imaging approaches to address one of the long-standing questions in chromosome biology: How do replisomes maintain efficiency and coordination during collisions with obstacles on the chromosome? Our objective is to develop a complete molecular understanding of the consequences of replisome collisions and the underlying mechanisms that allow for bypass or trigger replication fork collapse. We will begin this long-term research effort by addressing several issues fundamental to chromosome replication: How does replisome coordination and composition change during encounters with topological barriers in chromosomes? What are the dynamic events that underlie nucleosome disassembly by histone chaperones during replication? How does the eukaryotic replisome collaborate with histone chaperones to ensure faithful inheritance of epigenetic information encoded on histones? These studies will provide a framework for understanding the dynamics of replisome collisions and the molecular origin of chromosome damage underlying many diseases.