Small molecule modulation of the human chromatid decatenation checkpoint.
After chromosome replication, the intertwined sister chromatids are disentangled by topoisomerases. The integrity of this process is monitored by the chromatid decatenation checkpoint. Here, we describe small molecule modulators of the human chromatid decatenation checkpoint identified using a cell-based, chemical genetic modifier screen. Similar to 1,2,7-trimethylyxanthine (caffeine), these small molecules suppress the G(2)-phase arrest caused by ICRF-193, a small molecule inhibitor of the enzymatic activity of topoisomerase II. Analysis of specific suppressors, here named suptopins for suppressor of Topoisomerase II inhibition, revealed distinct effects on cell cycle progression, microtubule stability, nucleocytoplasmic transport of cyclin B1, and no effect on the chromatin deacetylation checkpoint induced by trichostatin A. The suptopins provide new molecular tools for dissecting the role of topoisomerases in maintaining genomic stability and determining whether inhibiting the chromatid decatenation checkpoint sensitizes tumor cells to chemotherapeutics.
Haggarty
Stephen J
SJ
Department of Molecular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Koeller
Kathryn M
KM
Kau
Tweeny R
TR
Silver
Pamela A
PA
Roberge
Michel
M
Schreiber
Stuart L
SL
D000107:Acetylation / Q000187:drug effects; D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002842:Chromatids / Q000187:drug effects* / Q000502:physiology*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D054659:Diketopiperazines; D005455:Fluorescent Antibody Technique; D018816:Genes, cdc; D006801:Humans; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D010879:Piperazines / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000627:Aminophenols; D001552:Benzazepines; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D054659:Diketopiperazines; D006877:Hydroxamic Acids; D010879:Piperazines; D011753:Pyrones; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; C489960:suptopin 1; C489961:suptopin 2; C489962:suptopin 3; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; C012589:trichostatin A; D004250:DNA Topoisomerases, Type II