New funding to explore the twists and turns of DNA
Professor David Sherratt is part of an exciting interdisciplinary research team that aims to explore a fundamental feature of DNA: how knots and links are removed so that newly replicated chromosomes can be faithfully segregated to daughter cells.
Dr Dorothy Buck, a mathematician from Imperial College, will lead the team which also includes Dr Sean Colloms from the University of Glasgow, Dr Andrzej Stasiak from Lausanne University, and artist Gemma Anderson.
Funding for the ambitious £1.74 million programme is from the Leverhulme Trust which ran an initiative requesting proposals on the theme of ‘Knots in Nature’.
DNA, like any other long piece of string packed into a small space, would become highly knotted without mechanisms to keep it organized. On top of this, the helical nature of DNA leads to a fundamental topological problem. The two strands are wrapped around each other every 10.5 base-pairs, 0.6 billion times in a human cell, and must be unlinked so the DNA can be segregated to daughter cells at every cell division.
Super-resolution in vivo tracking of a single topoisomerase molecule
Every living organism has developed machinery to keep the topology of DNA under control. Type II topoisomerases, for example, change topology by passing one duplex segment through another. Another set of enzymes, site-specific recombinases, takes on the task of knotting and linking DNA molecules during genetic recombination.
The interdisciplinary team will use a powerful combination of experimental, computational and mathematical approaches to answer fundamental problems in DNA knotting and linking as they relate to chromosome organization. A particular focus will be on understanding how topoisomersases and recombinases show topological selectivity and thereby act to shape and reshape chromosomes.
The work is important because some of the enzymes that regulate DNA topology are targets of anti-pathogen and anti-cancer drugs.
Professor Sherratt is an expert in single-molecule studies of bacterial chromosome organization, replication and segregation. He has played a central role in determining the topology of site-specific recombination reactions and relating this to biochemical mechanism.
With the development of super-resolution microscopy, he has pioneered quantitative live-cell imaging approaches for in vivo biochemistry and single-molecule studies of DNA interactions in vitro.
Knots in art
The experimental work in Oxford will focus on how the two intertwined strands of DNA are unlinked by topoisomerases during replication. Professor Sherratt says that the aim will be to develop mathematical descriptions of the knotting and unknotting process and to test the theories experimentally. Super-resolution microscopy provides a new and unparalleled approach to the experimental component.
He adds that although he has collaborated previously with Dr Colloms and Dr Stasiak, the Leverhulme programme has encouraged him to look in different directions to develop his work. Dr Buck has wet lab experience on top of her mathematical expertise, giving confidence that the different approaches within the programme will be tightly integrated.
Artist Gemma Anderson will add a further layer to the programme by exploring the connections between knots in mathematics, biology and art. The group hopes that the accompanying artwork and exhibitions will enable the public to engage with this intriguing topic.