The Impact of the C-Terminal Region on the Interaction of Topoisomerase II Alpha with Mitotic Chromatin

Many chemotherapy drugs target processes essential in dividing cells. One important target is the enzyme TOP2A, which plays a crucial role in maintaining genome stability and suppressing tumourigenesis. It accumulates on chromosomes during mitosis, and is essential for their compaction and segregation. The catalytic core of this protein has been extensively characterised. However, it is the catalytically-dispensable C-terminal third that confers this ability to accumulate on mitotic chromosomes.

In their new publication, Dr Melissa Antoniou-Kourounioti and Dr Michael Mimmack, working inĀ Dr Christine Farr's group in the Department of Genetics, identified several amino acids within the C-terminal domain whose modification is important for the interaction of TOP2A with mitotic chromosomes. Lysine 1240 is a major SUMO modification site, a process that is in turn affected by phosphorylation of nearby serine and threonine residues. Modification-blocking mutation of these sites (and of Lysine 662, another known SUMO acceptor) results in TOP2A being retained less efficiently at the centromere as cells progress through mitosis. The interaction of TOP2A with chromatin is very dynamic, with a high on/off exchange rate. The work reported identifies mutations that change this exchange rate, suggesting one mechanism by which SUMOylation and phosphorylation of TOP2A regulate its presence on mitotic chromosomes.

25 Mar 2019