Thomas Miller

• Presentation
• Research outputs

Our lab aims to understand the molecular mechanisms that maintain eukaryotic genome stability during DNA replication using a combination of genetic, biochemical, cellular, and structural techniques, including cryo-EM

Primary fields of research

The molecular mechanisms of faithful genome replication
Accurate chromosome replication is essential for controlled cell proliferation and the faithful transfer of genetic information from one generation to the next. A failure to maintain genome stability can cause diverse developmental disorders and age-related diseases, including accelerated neurodegeneration and cancer. Eukaryotic genomes are duplicated by large, multi-component protein machines called replisomes. At their core, replisomes consist of a helicase that unwinds duplex DNA and polymerases that catalyse the synthesis of new DNA molecules according to the parental template. A diverse range of accessory factors are also required facilitate the faithful replication of eukaryotic chromosomes, which contain an array of ‘obstacles’ that could otherwise stall or inhibit the replication machinery. Together, the replisome and accessory factors regulate the timing, speed and accuracy of replication, minimising replication errors and preventing genome instability. Our group aims to understand the molecular mechanisms by which eukaryotic replisomes and accessory factors preserve genome stability during DNA replication and how failures in these mechanisms cause disease. Ultimately, we plan to use the knowledge we gain to develop novel therapeutic approaches to prevent or treat human disorders linked to genome instability.

Current research

• The mechanisms and regulation of MCM helicase loading
• Replication-coupled DNA-protein crosslink (DPC) repair
• Accessory helicases in DNA replication
• Electron microscopy methods development – ‘Reconstitution in silico’ (RECONSIL)