Antitumor bisdioxopiperazines inhibit yeast DNAtopoisomerase II by trapping the enzyme in the form of a closed proteinclamp.

Roca, Joaquím; Ishida, Ryoji; Berger, James M.; Andoh, Toshiwo; Wang, James C.

doi:10.1073/pnas.91.5.1781

Cited by 303 publications

(290 citation statements)

References 20 publications

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Section: Dna Damage Induces Premitotic Cyclin B1 Nuclear Accumulationmentioning

confidence: 98%

“…Even though cyclin A-Cdk1/2 complexes were major targets of p21, we repeatedly observed a significant fraction of cyclin B1-Cdk1 complexes that was associated with this inhibitor (Baus et al, 2003). To better understand the role of this latter interaction, we followed by immunofluorescence the localization of p21 and cyclin B1 in synchronized NHF that were specifically arrested in G2 phase in the presence of ICRF-193 (Supplemental Figure 1A), a catalytic inhibitor of DNA topoisomerase II (Roca et al, 1994). Although earlier reports proposed that ICRF-193 does not induce double DNA strand breaks (Downes et al, 1994), distinct nuclear ␥-H2AX foci (Rogakou et al, 1999) could be detected in drug-treated cells (Supplemental Figure 2A), thus confirming recent observations (Mikhailov et al, 2002).…”

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confidence: 99%

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p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Charrier‐Savournin

Château

Gire

et al. 2004

MBoC

176

137

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G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest. INTRODUCTIONCyclin B1-Cdk1 is a master mitotic regulator and is therefore an ultimate target toward which most, if not all, antiproliferative signals generated during S and G2 phase converge. In cycling cells, cyclin B1 synthesis increases during late S-early G2 phase (Pines and Hunter, 1989), but the newly formed cyclin B1-Cdk1 complexes are kept inactive by inhibitory phosphorylations on Thr 14 and Tyr 15 (Norbury et al., 1991) and by active and constant nuclear exclusion via Crm1-mediated nuclear export (Hagting et al., 1998;Yang et al., 1998). The rapid nuclear accumulation of cyclin B1-Cdk1 that occurs in prophase coincides with phosphorylation of cyclin B1 at the cytoplasmic retention sequence, which also contains its nuclear export sequence (Hagting et al., 1999; for review, see Porter and Donoghue, 2003). Nuclear import of cyclin B1-Cdk1 coincides with Cdc25 phosphatase-mediated dephosphorylation of Thr 14 and Tyr 15 on Cdk1 (Berry and Gould, 1996). Based on these observations, it has been assumed that cytoplasmic cyclin B1-Cdk1 is not active. However, both earlier and most recent work suggest that cyclin B1-Cdk1 might already be activated in the cytoplasm and most probably at the centrosome (Heald et al., 1993;De Souza et al., 2000;Hirota et al., 2003;Jackman et al., 2003).According to the current model, signals elicited by DNA damage in S and G2 phases prevent mitotic entry by inhibiting both activation (via inactivation of Cdc25) and nuclear import of cyclin B1-Cdk1 (Jin et al., 1998;Yang et al., 1998Yang et al., , 2001Deming et al., 2001). G2 arrest is initiated via phosphorylation of Cdc25 by Chk1/2 kinases, a process that does not require active p53. On the other hand, the...

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Section: Dna Damage Induces Premitotic Cyclin B1 Nuclear Accumulationmentioning

confidence: 98%

mentioning

confidence: 99%

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Charrier‐Savournin

Château

Gire

et al. 2004

MBoC

176

137

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“…Among these remarkably simple molecules, (S)-4,4 0 -(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione (dexrazoxane, ICRF-187; Table 2) has been approved for use in cancer patients to prevent anthracycline-mediated cardiotoxicity [68]. Intriguingly, dexrazoxane inhibits DNA topoisomerase II by stabilizing the closed conformation of the homodimeric enzyme [69]. Elucidation of the crystal structure for the topoisomerase II dimer complexed with dexrazoxane indicated how dexrazoxane bound to a composite, symmetric pocket in the interface of the topoisomerase II homodimer and contacts both monomers simultaneously at the exact corresponding sites in the antiparallel dimer [70].…”

Section: Dexrazoxanementioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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“…Studies with these topo II poisons precluded the discovery of the decatenation checkpoint. In contrast, the catalytic inhibitors, which include ICRF-193 and related bisdioxopiperazines, inhibit topo II before DSB formation and activate the decatenation checkpoint, but not the DNA damage checkpoint (Downes et al, 1994;Roca et al, 1994). The decatenation checkpoint is typically studied with the bisdioxopiperazine topo II inhibitors.…”

Section: Function Of the Decatenation Checkpointmentioning

confidence: 99%

The decatenation checkpoint

Damelin

Bestor

2007

Br J Cancer

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The decatenation checkpoint delays entry into mitosis until the chromosomes have been disentangled. Deficiency in or bypass of the decatenation checkpoint can cause chromosome breakage and nondisjunction during mitosis, which results in aneuploidy and chromosome rearrangements in the daughter cells. A deficiency in the decatenation checkpoint has been reported in lung and bladder cancer cell lines and may contribute to the accumulation of chromosome aberrations that commonly occur during tumour progression. A checkpoint deficiency has also been documented in cultured stem and progenitor cells, and cancer stem cells are likely to be derived from stem and progenitor cells that lack an effective decatenation checkpoint. An inefficient decatenation checkpoint is likely to be a source of the chromosome aberrations that are common features of most tumours, but an inefficient decatenation checkpoint in cancer stem cells could also provide a potential target for chemotherapy.

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Antitumor bisdioxopiperazines inhibit yeast DNAtopoisomerase II by trapping the enzyme in the form of a closed proteinclamp.

Cited by 303 publications

References 20 publications

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Stabilization of protein–protein interactions by small molecules

The decatenation checkpoint

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