Entanglements in DNA occur during
replication, repair, and recombination. These
chromosomal entanglements can lead to cell death if
chromosomes are not able to separate during cell
division2. For this reason, research
concerning topoisomerase II has serious implications
for cancer treatment. For example, the anticancer
agent ICRF-187 binds to topo II and causes a
conformational change that renders the enzyme
inactive. Specifically, ICRF-187 targets topo II
that has already formed bonds with ATP and DNA. It
binds to the 14 residue drug-binding pocket, and
bridges the two ATPase domains together3.
The stabilization of the ATPase domains essentially
converts topo II into a clamp on the DNA that
prevents it from being disentangled or released.
1. Schmidt B.H., Osheroff N.,
and Berger J.M. 2012. Structure of a topoisomerase
II/ DNA/nucleotide complex reveals a new control
mechanism for ATPase activity. Nature Structural
& Molecular Biology, 19(11): 1147 - 1154.
2. Berger J.M., Gamblin S.J.,
Harrison S.C., and Wang J.C. 1996. Structure and
mechanism of DNA topoisomerase II. Nature,
379: 225 - 232.
3. Classen S., Olland S., and
Berger J.M. 2003. Structure of the topoisomerase
II ATPase region and its mechanism of inhibition
by the chemotherapeutic agent ICRF-187.Proc.
Natl. Acad. Sci. U.S.A., 100(19): 10629 -
4. Berger J.M. and Wang J.C.
1996. Recent developments in DNA topoisomerase II
structure and mechanism. Curr. Opin. Struct.
Biol. 6(1): 84 - 90.
5.Deweese J.E., and Osheroff
N. 2009. The DNA cleavage reaction of
topoisomerase II: wolf in sheep's clothing.Nucl.
Acids Res. 37(3):738-748.
6.Schmidt B.H., Burgin A. B.,
Deweese J.E., Osheroff N., Berger J.M. 2010. A
novel and unified two-metal mechanism for DNA
cleavage by type II and IA topoisomerases.Nature,
465(7298): 641 - 644.
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