Non-Catalytic Roles of the Topoisomerase IIα C-Terminal Domain

Abstract

DNA Topoisomerase IIα (Topo IIα) is a ubiquitous enzyme in eukaryotes that performs the strand passage reaction where a double helix of DNA is passed through a second double helix. This unique reaction is critical for numerous cellular processes. However, the enzyme also possesses a C-terminal domain (CTD) that is largely dispensable for the strand passage reaction but is nevertheless important for the fidelity of cell division. Recent studies have expanded our understanding of the roles of the Topo IIα CTD, in particular in mitotic mechanisms where the CTD is modified by Small Ubiquitin-like Modifier (SUMO), which in turn provides binding sites for key regulators of mitosis.

Keywords: Aurora B; C-terminal domain; Claspin; Haspin; SUMO; Topoisomerase II; metaphase checkpoint; mitosis.

Figure 1

Top: Strand Passage Reaction. (i) G-segment DNA binds at catalytic core (orange/yellow/red), (ii) T-segment DNA captured by N-gate (purple/blue), G-segment cleavage, (iii) T-segment transport, G-segment ligation, (iv) T-segment release from C-gate (green). Bottom: Domain structure (colors match domains above). C-terminal domain (CTD; grey) has not been crystalized.

Figure 2

Components of the human Topo IIα CTD: (a) 200 a.a. CTD (grey box); the last 31 residues define the Chromatin Tether (ChT) domain (shaded blue). ChT domain (blue box) with Acid-Patch nested serine motif (A-S-P; red) and the upstream cluster of Lysine (cLys) residues (orange box); (b) conserved ChT residues (yellow) of Topo II adjacent to the A-S-P motif (red).

Figure 3

Comparison of Topoisomerase II (Topo II) poisoning (left) versus catalytic inhibition (right). DNA color scheme: Black helix (G-segment DNA); Red helix (T-segment DNA). Topo II domains: N-gate (purple/blue); DNA-binding catalytic core (orange/yellow/red); C-gate (green).