Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Bacterial genome organisation by DNA topology remodelling machines

Funder Wellcome Charity-funded
Recipient organisation MRC Laboratory of Molecular Biology
Funding £3.5M
Period Apr 2024 — Apr 2032

In plain English

AI plain-English summary

Every second, bacteria must pack two metres of DNA into a cell a thousand times smaller than a grain of salt—and they do it using a protein machine called MukBEF. This project uses high-resolution cryo-electron microscopy to reveal exactly how MukBEF grabs, loops, and compacts DNA, and how it teams up with a second protein, TopoIV, to separate newly copied chromosomes and defend against invading plasmids. The fundamental gap is that scientists know these machines exist but do not understand the molecular choreography that makes them work. This is fundamental science with no immediate practical application. However, the same MukBEF family of proteins—SMC complexes—operates in human cells, where their failure causes chromosome shattering and cancer. A complete structural picture of how a bacterial SMC complex extrudes DNA loops and coordinates with topoisomerases will illuminate the basic principles of genome organisation across all life. That deeper understanding could eventually guide efforts to disrupt bacterial chromosome segregation in new antibiotics, or to understand what goes wrong when human SMC complexes malfunction in disease.

View original technical description
Structural maintenance of chromosomes (SMC) complexes help to shape, segregate and guard the genome in prokaryotes and eukaryotes. How they execute these different functions at the molecular level remains unclear. I have pioneered the high-resolution electron cryo-microscopy (cryo-EM) analysis of the bacterial SMC complex MukBEF, which revealed a snapshot of its interaction with chromosomal DNA. I will now build upon my findings with a multi- disciplinary approach to ask: (i) how MukBEF extrudes DNA loops to compact and shape bacterial chromosomes; and (ii) how MukBEF cooperates with topoisomerase family proteins such as TopoIV to segregate replication origins and protect cells from plasmid infection. I will use in vitro reconstitution to study the genome organisation reaction by biochemistry and cryo-EM, aiming for a full structural understanding of its molecular mechanism. I will clarify the regulation by cellular housekeeping factors. I will determine the mechanism of MukBEF–TopoIV supercomplex formation and establish how two fundamentally conserved chromosome segregation factors join forces. In addition, I will resolve how MukBEF homologues activate the topoisomerase-like MksG to sense and eliminate infective plasmids. This work will deliver unprecedented new insights into bacterial chromosome biology and inform related processes in eukaryotes.

View the original record at the funder ↗

Researchers

Frank Bürmann (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Coordination of chromosome unlinking and segregation
Balancing Dissolution and Resolution / Finding a Solution
Probing the mechanisms that couple genome segregation to chromosome organization in Archaea
Investigating the interplay between SMC complexes and Topoisomerase II
How does Structural Maintenance of Chromosomes (SMC) protein interact with DNA to organise bacterial chromosomes?

Original classification

Career Development Award

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.