Protein Sciences in Drug Discovery 2022

Building the replisome: structure and mechanism of a DNA replication machine

Wed2  Nov04:25pm(30 mins)
The Auditorium
Dr Joe Yeeles


Accurate chromosome is essential to maintain genomic integrity in dividing cells. The protein machinery responsible for this vital task is collectively termed the replisome. The replisome is organised around the 11-subunit CMG (Cdc45-MCM-GINS) replicative helicase complex that is assembled and activated at sites across the genome termed replication origins. Once activated, many additional proteins, including multiple DNA polymerases, associate with CMG to initiate DNA replication. My lab uses a combination of sophisticated biochemical reconstitution, cryo-EM and yeast genetics to discover key mechanisms that underpin faithful genome duplication by the yeast replisome. Moreover, recently we have for the first time reconstituted a functional human replisome entirely from purified proteins that can perform fast and efficient leading- and lagging-strand DNA replication and have also determined the structure of the core human replisome using cryo-EM. I will present our recent discoveries made using these cutting-edge systems.

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