Ubiquitylation and sumoylation are essential tools for modulating the function of proteins involved in the response to DNA damage. A series of specialised enzymes: E1, E2 and E3 covalently attach single or multiple ubiquitin or SUMO moieties to target proteins most often via lysine residues. All of the seven lysine residues of ubiquitin can be used for further ubiquitylation resulting in the formation of ubiquitin chains. In addition, there are three forms of SUMO (1,2 and 3). All these create a wide scope for the functional complexity of ubiquitin and SUMO signalling.
The role of ubiquitylation in regulation of chromosomal replication – especially the termination stage of replication
To ensure faultless duplication of the whole genome, DNA replication initiates from thousands of origins of replication. An origin fires when the replicative helicase is activated and starts to unwind double stranded DNA creating two DNA replication forks. The progressing replication fork moves through the chromatin until it encounters a fork from the neighbouring origin. When the forks converge (the termination of replication forks) the replisomes disassemble by an unknown mechanism and topisomerase II resolves the daughter DNA molecules. If not resolved properly, the terminating forks are at high risk of stalling and fork reversal, leading to DNA damage and genomic instabilities.
We are investigating the mechanism of replisome disassembly at the termination stage of DNA replication and the role of ubiquitylation in this process. (Model)
The role of SUMO in regulation of chromosomal replication
The process of sumoylation resembles closely this of ubiquitylation, but the role of SUMO modification during DNA replication and damage are much less understood. We aim therefore to identify replication factors modified my SUMO during the process of replication and characterise the function of these modifications.