scholarly journals Cell Cycle-Dependent Control and Roles of DNA Topoisomerase II

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 859 ◽  
Author(s):  
Joyce H. Lee ◽  
James M. Berger
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Type Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Cycle Progression ◽  
Double Stranded Dna ◽  
Topo Ii ◽  
Cycle Dependent

Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development.

DNA topoisomerase II-dependent control of the cell cycle progression in root meristems ofAllium cepa

2013 ◽  
Vol 38 (3) ◽  
pp. 355-367 ◽  
Author(s):  
Aneta Żabka ◽  
Justyna Teresa Polit ◽  
Joanna Bernasińska ◽  
Janusz Maszewski
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Cycle Progression ◽  
Root Meristems ◽  
Ofallium Cepa

During both interphase and mitosis, DNA topoisomerase II interacts with DNA as well as RNA through the protein's C-terminal domain

2000 ◽  
Vol 113 (9) ◽  
pp. 1635-1647
Author(s):  
R. Rzepecki ◽  
P.A. Fisher
Keyword(s):  
Nucleic Acid ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Terminal Domain ◽  
Highly Active ◽  
Topo Ii ◽  
Cycle Dependent ◽  
Nucleic Acid Interactions

DNA topoisomerase II (topo II) is thought to be a nuclear enzyme; during interphase most was insoluble and could be recovered in the pellet after centrifugation of cell homogenates at 10,000 g (P-10). Upon entry into mitosis, the majority of topo II did not associate with condensed chromosomes but was apparently solubilized and redistributed throughout the cell. Although two non-chromosomal subfractions of mitotic topo II were defined by centrifugation at 130,000 g, the vast majority (>90%) was recovered in the pellet (P-130). In vivo nucleic acid interactions with topo II were monitored by a recently developed approach of UV-photo-crosslinking, immunoprecipitation and (32)P-labeling. P-10 (interphase) topo II was largely associated with DNA. P-130 (mitotic non-chromosomal) topo II was primarily associated with RNA. These nucleic acid interactions with both interphase and mitotic topo II occurred through the catalytically inert and as yet, poorly understood C-terminal domain of the protein. P-10 topo II was highly active enzymatically. Activity, measured by the ability of topo II to decatenate kDNA minicircles, was reduced by treatment with phosphatase. In contrast, P-130 topo II was relatively inactive but activity could be increased by phosphatase treatment. In vivo, P-130 topo II was more heavily phosphorylated than P-10 topo II; in both, only the C-terminal domain of topo II was detectably modified. Our observations suggest that cell cycle-dependent changes in the distribution, nucleic acid interactions and enzymatic activity of topo II are regulated, at least in part, by phosphorylation/dephosphorylation.

Potent cytotoxicity and inhibition of pan-cell cycle progression by Alchemix, a novel alkylating anthraquinone

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12030-12030
Author(s):  
A. A. Epenetos ◽  
K. Pors ◽  
P. J. Smith ◽  
L. H. Patterson
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Topoisomerase Ii ◽  
Human Tumors ◽  
Drug Resistant ◽  
Cycle Progression ◽  
Topo Ii

12030 Introduction: DNA topoisomerase II (topo II) is crucial to the maintenance of cancer cells in a proliferative state. DNA intercalation is a crucial part of topo II inhibition by DNA affinic anthraquinones. Potent cytotoxicity of anthraquinones, is related to their slow rate of dissociation from DNA, the kinetics of which favours long-term trapping of the topo-DNA complexes. Currently available DNA interacting agents at best promote a transient inhibition of topo II, since the topo-drug-DNA ternary complex is reversed by removal of the intracellular drug pool. Results: Alchemix cell cycle events: DNA content and Cyclin B1 expression were measured using flow cytometry and a p53 functional human osteosarcoma cell line (U2-OS) The results indicate: (ii) slow pan-cell cycle progression and mitotic commitment with a limited expression of G2 arrest, (iii) B1 cyclin tracking reveals that escape from Alchemix-induced cell cycle arrest in G2 is forcing some cells to enter polyploidy via an aberrant mitosis in keeping with topoisomerase II inhibition. Alchemix in vitro activity against the NCI human cell line panel including several drug resistant cancer cell lines had a mean IG50 = 49 nM. 11 of the 24 cell lines tested have an IG50 of <10 nM. Alchemix retains potent activity against chemotherapy resistant tumors including drug resistant ones. Conclusions: Alchemix possesses potent activity across a variety of different human tumors and significantly shows potent activity in cisplatin and anthracyline resistant human tumors Alchemix has pan-cell cycle effects. Multilevel targeting by Alchemix reduces the probability of evasion of cell cycle related pharmacodynamic responses. Results help explain the activity of Alchemix in both cisplatin and anthracycline resistant tumors in vitro and in vivo. [Table: see text]

Exogenous ATP induces a limited cell cycle progression of arterial smooth muscle cells

1993 ◽  
Vol 264 (4) ◽  
pp. C783-C788 ◽  
Author(s):  
R. Malam-Souley ◽  
M. Campan ◽  
A. P. Gadeau ◽  
C. Desgranges
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Mrna Level ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Cycle Progression ◽  
Arterial Smooth Muscle Cells ◽  
Cycle Dependent

Because exogenous ATP is suspected to influence the proliferative process, its effects on the cell cycle progression of arterial smooth muscle cells were studied by investigating changes in the mRNA steady-state level of cell cycle-dependent genes. Stimulation of cultured quiescent smooth muscle cells by exogenous ATP induced chronological activation not only of immediate-early but also of delayed-early cell cycle-dependent genes, which were usually expressed after a mitogenic stimulation. In contrast, ATP did not increase late G1 gene mRNA level, demonstrating that this nucleotide induces a limited cell cycle progression of arterial smooth muscle cells through the G1 phase but is not able by itself to induce crossing over the G1-S boundary and consequently DNA synthesis. An increase in c-fos mRNA level was also induced by ADP but not by AMP or adenosine. Moreover, 2-methylthioadenosine 5'-triphosphate but not alpha, beta-methyleneadenosine 5'-triphosphate mediated this kind of response. Taken together, these results demonstrate that extracellular ATP induces the limited progression of arterial smooth muscle cells through the G1 phase via its fixation on P2 gamma receptors.

scholarly journals Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA- topoisomerase II

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3705-3711 ◽  
Author(s):  
HJ Super ◽  
NR McCabe ◽  
MJ Thirman ◽  
RA Larson ◽  
MM Le Beau ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Chromosome Band ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Mll Gene ◽  
Topo Ii ◽  
Acute Myeloid

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

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