Termination of DNA replication: mechanism and importance

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA replication must be precisely regulated as unrepaired mistakes can change cell behaviour with potentially severe consequences, such as genetic disease, cancer and premature ageing. Fundamental studies by many labs have led to a step-change in our understanding of the initiation of DNA replication and DNA synthesis, but until our discovery of the first elements of the eukaryotic replisome disassembly mechanism in 2014, the termination stage of replication was mostly unexplored.
Perturbations in DNA replication initiation and elongation leading to genomic instability are linked with genetic disorders and can drive cancer development. Moreover, both processes are targeted by many cancer therapies (e.g. cisplatin, gemcitabine, topotecan). Data from simpler model systems (yeast and C.elegans) and our preliminary work in human cells indicate that perturbations of replisome disassembly also lead to DNA damage. The disruption of replisome disassembly is, therefore, highly likely to be detrimental to human health, but so far nobody has investigated this process.
Our work therefore aims to unravel the molecular mechanisms of replisome disassembly. We also wish to determine how genomic instability is created upon failure of this process. We carry on our work in a two-pronged approach: (i) through detailed biochemical dissection of the protein complexes driving this process in a cell-free Xenopus laevis egg extract system, followed by (ii) validation of the role of these complexes and investigations of the consequences of their disruption in human immortalized cell lines. Our work aims therefore not only elucidate the molecular mechanism of the fundamental process of replication termination, but will also set the stage to exploit this knowledge for our understanding of genomic instability as a major cause of cancer.