New protective mechanism preventing premature termination of chromosome replication defined

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Through this work recently published in Nature, the team have defined a new protective mechanism that cells use to prevent the premature termination of chromosome replication.

The process of chromosome replication, which frequently goes wrong in human diseases such as cancer, is carried out by a molecular machine called the replisome. The replisome is assembled on chromosomes at the start of chromosome replication and is only disassembled once replication is complete. Disassembly is triggered by ubiquitylation of the replisome; the regulatory mechanism that restricts ubiquitylation to only those replisomes that have finished replication has been a major unanswered question for the past decade.

The research team - Tom Deegan (now at MRC Human Genetics Unit, previously with Karim Labib at the MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee), Joe Yeeles, Michael Jenkyn-Bedford and Morgan Jones (MRC Laboratory of Molecular Biology, Cambridge) - used cryo-electron microscopy to solve structures of the replisome in complex with the E3 ubiquitin ligase that drives replisome ubiquitylation.

These structures identified a previously undescribed replisome-E3 ligase interaction that is blocked by a DNA structure called the ‘excluded strand’, which is present at active replisomes but disappears when replication has finished.

Remarkably, despite using completely different E3 ubiquitin ligases for replisome ubiquitylation, this regulatory mechanism is conserved between yeast and humans.

In addition to defining the molecular mechanism of a fundamental step in chromosome replication, this work may also have implications for our understanding of the origins of cancer and some developmental disorders, which are frequently associated with replisome disfunction and errors in the chromosome replication process.

I’m really excited about this collaborative study with Joe Yeeles’ lab, as it provides a molecular answer to a longstanding question in the chromosome replication field. I am very thankful to my collaborators Michael Jenkyn-Bedford, Morgan Jones and Joe Yeeles – this has been a very enjoyable team effort, which was dependent on our complementary expertise.

The mechanism we describe for regulating replisome disassembly throws up a new set of really interesting questions for us to focus on, which will form part of the research programme that I will bring to MRC HGU. Given the Unit’s focus and wide ranging expertise, I also hope to be able to understand some of my fundamental research discoveries in the context of the numerous human diseases that are associated with replisome disfunction.

Dr Tom Deegan

Tom Deegan joined the MRC Human Genetics Unit as Group Leader in September 2021. Tom brings outstanding biochemistry expertise to the Unit through his previous work at the MRC PPU and CRUK Clare Hall Laboratories. His lab investigates the fundamental mechanisms that cells use to replicate their chromosomes, and how these mechanisms contribute to stable genome inheritance between cells and between generations. His work with the Unit hopes to shed new light on chromosome replication, and how errors in this process can lead to developmental disorders and cancers.

Links

• A Conserved Mechanism for Regulating Replisome Disassembly in Eukaryotes, published in Nature, 26 October 2021: https://www.nature.com/articles/s41586-021-04145-3 
• Tom Deegan Research Group