Cell cycle stage-dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity

Estey, Elihu H.; Adlakha, Ramesh C.; Hittelman, Walter N.; Zwelling, Leonard A.

doi:10.1021/bi00388a023

Cited by 86 publications

(24 citation statements)

References 30 publications

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“…The same conclusion of a role for topoisomerase II in decatenation was proposed in the case of rDNA minichromosomes, for which we found enhanced topoisomerase II cleavage although transcription was off (26). It is noteworthy that early experiments using alkaline elution suggested that overall DNA cleavage induced by topoisomerase II poisons in mammalian cells was considerably increased during mitosis (38,39). In the same way, since the gene is replicated during the first 10 min of S phase, it is tempting to speculate that occurrence of topoisomerase II sites at this time correlates with rapid chromosome decondensation after metaphase, to allow replication fork passage throughout this region.…”

Section: Discussionsupporting

confidence: 85%

DNA topoisomerase II sites in the histone H4 gene during the highly synchronous cell cycle of Physarum polycephalum

Borde¹,

Duguet²

1998

Nucleic Acids Research

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The nearly perfect synchrony of nuclear division in a plasmodium of Physarum polycephalum provides a powerful system to analyze topoisomerase II cleavage sites in the course of the cell cycle. The histone H4 locus, whose schedule of replication and transcription is precisely known, was chosen for this analysis. Drug-induced topoisomerase II sites are clustered downstream of the histone H4 gene and appear highly dependent on cell cycle stage. They were only detected in mitosis and at the very beginning of S phase, precisely at the time of replication of the histone H4 region. The sites, which were absent in G2 phase, reappeared at the next mitosis. Remarkably, DNase I hypersensitive sites occurred in nearly the same location, but their schedule was totally different: they were absent in mitosis and present in G2. This schedule follows H4 transcription, which peaks in mid-S phase and in the second part of G2 phase and is off during mitosis. These results suggest that topoisomerase II may not be involved in transcription, but plays a role in remodeling chromatin structure, both during chromosome condensation in prophase/metaphase to allow their decatenation and during chromosome decondensation after metaphase to allow replication fork passage throughout the region.

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Section: Discussionsupporting

confidence: 85%

DNA topoisomerase II sites in the histone H4 gene during the highly synchronous cell cycle of Physarum polycephalum

Borde¹,

Duguet²

1998

Nucleic Acids Research

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“…Iftopoisomerase II were phosphorylated during mitosis, one would expect an ==10-fold increase in activity (taking into account the increase in enzyme content prior to mitosis). In fact, 4-to 15-fold more topoisomerase II activity was detected in mitotic HeLa cells than in an S-phase population (38). Phosphorylation may be responsible for rapid changes in activity in response to intracellular signals, whereas alterations in the amount of protein may be required for the gross structural reorganization of the genome during mitosis.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle.

Heck

Hittelman

Earnshaw

1988

Proc. Natl. Acad. Sci. U.S.A.

364

196

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We have utilized antibody probes to examine the expression of DNA topoisomerases I and II and chromosome scaffold protein Sc-2 in normal and transformed cells. Neither topoisomerase I nor Sc-2 shows significant fluctuations in content or stability across the cell cycle. In contrast, topoisomerase II undergoes significant cell cycle-dependent alterations in both amount and stability. As cells progress from mitosis into G1, much of the topoisomerase II is degraded. During the first 2 hr of G1, the half life of topoisomerase II is decreased from that measured in asynchronous cell populations by a factor of 7. This suggests that the chromosome condensation/decondensation cycle is coupled to a parallel cycle of synthesis and degradation of topoisomerase II. In control experiments, we also found that the half-life of topoisomerase II is shorter in normal cells than in transformed cells by a factor of 4. Since the number of copies of topoisomerase II per cell is also lower in normal cells, this suggests that control of topoisomerase II stability is altered upon transformation. The stability of topoisomerase I and Sc-2 does not differ significantly between normal and transformed cells. (6)(7)(8).Topoisomerase I is apparently not a structural protein, as it is extractable from chromatin at relatively low ionic strength (9) and is distributed throughout the large =100-kilobase (kb) chromatin loops of the mitotic chromosome (5). In addition, topoisomerase I is not essential for growth in yeast (6,10,11).Assays of topoisomerase II activity both in cell-free extracts and in vivo suggested that enzyme levels are greater in proliferating cells than in their quiescent counterparts (12)(13)(14)(15)(16)(17). Quantitative immunological methods demonstrated that topoisomerase II is rapidly lost upon cessation of mitotic activity in either immature erythroblasts or myoblasts (18), thus confirming that the enzyme is a specific and sensitive marker for cell proliferation. Topoisomerase I, on the other hand, is present in many different quiescent cell types (12, 18).The disappearance of topoisomerase II upon the cessation of mitotic activity suggested to us that the transition from mitosis to interphase might be accompanied by facilitated degradation of this protein. Therefore, we have used antibody probes to examine the expression and stability of the enzyme across the cell cycle, with particular emphasis on the period surrounding mitosis. As controls, we performed parallel studies on topoisomerase I and on Sc-2, a 135-kDa polypeptide that is the second most abundant component of the mitotic chromosome-scaffold fraction (19). The results indicate that the transition from mitosis into the subsequent G1 phase is accompanied by a dramatic decrease in the stability of topoisomerase II (but not topoisomerase I or Sc-2). These observations suggest that degradation of topoisomerase II may be intimately associated with the process of chromosome decondensation. tTo whom reprint requests should be addressed. MATERIALS AND METHODS 1086T...

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“…A number of investigators have demonstrated a dissociation between drug-induced DNA cleavage and cytotoxicity in the various stages of the cell cycle. Estey et al (1987) reported that in HeLa cells maximum DNA cleavage was produced in mitosis, whereas maximum cytotoxicity occurred in S-phase cells. Similar observations have been reported in 3T3 cells (Chow & Ross, 1987;Markovits et al, 1987).…”

Section: Cellular Recognition Of Dna Damagementioning

confidence: 99%

Multidrug Resistance in Leukaemia

McKenna

Padua

1997

Br J Haematol

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Cell cycle stage-dependent variations in drug-induced topoisomerase II mediated DNA cleavage and cytotoxicity

Cited by 86 publications

References 30 publications

DNA topoisomerase II sites in the histone H4 gene during the highly synchronous cell cycle of Physarum polycephalum

DNA topoisomerase II sites in the histone H4 gene during the highly synchronous cell cycle of Physarum polycephalum

Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle.

Multidrug Resistance in Leukaemia

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