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

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

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.
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Host institution

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV

Address

Hofgartenstrasse 8
80539 Muenchen

Germany

Activity type

Research Organisations

EU Contribution

€ 1 500 000

Beneficiaries (1)

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MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV

Germany

EU Contribution

€ 1 500 000

Project information

Grant agreement ID: 804098

Status

Ongoing project

  • Start date

    1 January 2019

  • End date

    31 December 2023

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 500 000

  • EU contribution

    € 1 500 000

Hosted by:

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV

Germany