Topoisomerases play crucial roles in
DNA metabolism that include replication, transcription, recombination, and
chromatin structure by manipulating
DNA structures arising in
double-stranded DNA. These
proteins play key enzymatic roles in a variety of cellular processes and are also likely to play structural roles. Topoisomerases allow topological transformations by introducing transient breaks in
DNA by a transesterification reaction between a
tyrosine residue of the
enzyme and
DNA. The cleavage reaction leads to a unique
enzyme intermediate that allows cutting
DNA while minimizing the potential for damage-induced genetic changes. Nonetheless, topoisomerase-mediated cleavage has the potential for inducing
genome instability if the
enzyme-mediated
DNA resealing is impaired. Regulation of topoisomerase functions is accomplished by post-translational modifications including phosphorylation, polyADP-ribosylation, ubiquitylation, and SUMOylation. These modifications modulate
enzyme activity and likely play key roles in determining sites of
enzyme action and enzyme stability. Topoisomerase-mediated DNA cleavage and rejoining are affected by a variety of conditions including the action of small molecules, topoisomerase mutations, and
DNA structural forms which permit the conversion of the short-lived cleavage intermediate to persistent topoisomerase
DNA-
protein crosslink (TOP-DPC). Recognition and processing of TOP-DPCs utilizes many of the same post-translational modifications that regulate
enzyme activity. This review focuses on SUMOylation of topoisomerases, which has been demonstrated to be a key modification of both type I and type II topoisomerases. Special emphasis is placed on recent studies that indicate how SUMOylation regulates topoisomerase function in unperturbed cells and the unique roles that SUMOylation plays in repairing damage arising from topoisomerase malfunction.