Topoisomerase II is an essential
enzyme that plays critical roles in many
DNA processes, including chromosome segregation. In order to carry out its important physiological functions,
topoisomerase II creates and rejoins double-stranded breaks in the genetic material. Thus, while the
enzyme is necessary for cell survival, it also has the capacity to fragment the genome.
Topoisomerase II-mediated DNA breaks are sequestered within a covalent
enzyme-
DNA complex. Normally, these "cleavage complexes" are present at low levels and are tolerated by the cell. However, conditions that significantly increase the physiological concentration or life-time of
topoisomerase II-DNA cleavage complexes lead to
chromosomal translocations and other mutagenic events, and can induce cell death pathways. The potentially lethal aspect of
enzyme mechanism has been exploited by a number of highly successful
anticancer agents. Since drugs that increase levels of
topoisomerase II-DNA cleavage complexes transform the
enzyme into a potent cellular toxin, they are referred to as
topoisomerase II "
poisons" to distinguish them from compounds that inhibit the catalytic activity of the
enzyme. Recent evidence indicates that many DNA lesions also act as
topoisomerase II poisons. This finding has provided tremendous insight into
enzyme and
drug action and raises important questions regarding the physiological interactions of
topoisomerase II with DNA damage. Since the DNA cleavage and
ligation reactions of
topoisomerase II are fundamental to its physiological and pharmacological functions, this review will focus on how the
enzyme cuts and rejoins the double helix and how these reactions are altered by
topoisomerase II poisons.