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Challenges on the road to genome duplication: Single-molecule approaches to study replisome collisions

Project description

Fundamental mechanisms of chromosome replication

Faithful duplication and transmission of genetic and epigenetic information inside living cells are conducted by large macromolecular complexes known as the replisomes, which coordinate the enzymatic events during chromosome duplication. The EU-funded REPLISOMEBYPASS project aims to develop a single-molecule imaging approach to study the mechanisms by which replisomes maintain efficiency and coordination during collisions with obstacles on the chromosome. The project capitalises on a recently developed multidimensional, single-molecule imaging approach for the real-time visualisation of coordination during replication. The objective is to understand the consequences of replisome collisions and the mechanisms that allow bypassing or triggering replication fork collapse. The project’s work will uncover the molecular origin of chromosome damage underlying many diseases.

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.

Host institution

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Net EU contribution
€ 1 500 000,00
Address
HOFGARTENSTRASSE 8
80539 Munchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Research Organisations
Links
Total cost
€ 1 500 000,00

Beneficiaries (1)