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Advisor(s)
Abstract(s)
Type 2 topoisomerases, in particular the A isoform in human
cells, play a key role in cohesion and sister chromatid separation
during mitosis. These enzymes are thus vital for cycling cells
and are obvious targets in cancer chemotherapy. Evidence
obtained in yeast and Xenopus model systems indicates that
conjugation of topoisomerase 2 with small ubiquitin-like
modifier (SUMO) proteins is required for its mitotic functions.
Here, we provide biochemical and cytologic evidence that
topoisomerase 2A is conjugated to SUMO-2/3 during interphase
and mitosis in response to topoisomerase 2 inhibitors and
‘‘poisons’’ (ICRF-187, etoposide, doxorubicin) that stabilize
catalytic intermediates (cleavage complexes, closed clamp
forms) of the enzyme onto target DNA. During mitosis, SUMO-
2/3–modified forms of topoisomerase 2A localize to centromeres
and chromosome cores/axes. However, centromeres are
unresponsive to inhibitors during interphase. Furthermore,
formation of topoisomerase 2A–SUMO-2/3 conjugates within
mitotic chromosomes strongly correlates with incomplete
chromatid decatenation and decreases progressively as cells
approach the metaphase-anaphase transition. We also found
that the PIASy protein, an E3 ligase for SUMO proteins,
colocalizes with SUMO-2/3 at the mitotic chromosomal cores/
axes and is necessary for both formation of SUMO-2/3
conjugates and proper chromatid segregation. We suggest that
the efficacy of topoisomerase inhibitors to arrest cells traversing
mitosis may relate to their targeting of topoisomerase 2A–
SUMO-2/3 conjugates that concentrate at mitotic chromosome
axes and are directly involved in chromatid arm separation.
[Cancer Res 2008;68(7):2409–18]
Description
Keywords
Cancer Topoisomerase IIα SUMO Cell cycle