DNA topoisomerase II alpha is the major chromosome protein recognized by the mitotic phosphoprotein antibody MPM-2.

Taagepera, Salme; Rao, Potu N.; Drake, Fred H.; Gorbsky, Gary J.

doi:10.1073/pnas.90.18.8407

Cited by 157 publications

(120 citation statements)

References 38 publications

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“…To fulfill these latter responsibilities, the enzyme appears to act at specific regions in the genetic material (matrix/scaffold attachment regions (i.e. MAR and SAR sequences) and centromeric sequences, for example) (27,48,53,54). Thus, against a background of low stringency sites, topoisomerase II may have highly preferred sites of action within the genome.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites

Burden¹,

Osheroff

1999

Journal of Biological Chemistry

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Topoisomerase II is an essential enzyme that is the target for several clinically important anticancer drugs. Although this enzyme must create transient doublestranded breaks in the genetic material in order to carry out its indispensable DNA strand passage reaction, the factors that underlie its nucleotide cleavage specificity remain an enigma. Therefore, to address the critical issue of enzyme specificity, a modified systematic evolution of ligands by exponential enrichment (SELEX) protocol was employed to select/evolve DNA sequences that were preferentially cleaved by Drosophila melanogaster topoisomerase II. Levels of DNA scission rose substantially (from 3 to 20%) over 20 rounds of SELEX. In vitro selection/evolution converged on an alternating purine/pyrmidine sequence that was highly AT-rich (TATATATACATATATATA). The preference for this sequence was more pronounced for Drosophila topoisomerase II over other species and was increased in the presence of DNA cleavage-enhancing anticancer drugs. Enhanced cleavage appeared to be based on higher rates of DNA scission rather than increased binding affinity or decreased religation rates. The preferred sequence for topoisomerase II-mediated DNA cleavage is dramatically overrepresented (ϳ10,000-fold) in the euchromatic genome of D. melanogaster, implying that it may be a site for the physiological action of this enzyme.

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Section: Discussionmentioning

confidence: 99%

In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites

Burden¹,

Osheroff

1999

Journal of Biological Chemistry

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“…Thus cdc2 interacts with topoisomerase II, and, moreover, proliferating cell nuclear antigen, the cellular homolog of U L 42, mediates cyclindependent kinase substrate phosphorylation (8)(9)(10)(11)(12). Topoisomerase II is of particular interest because it is one of the key enzymes required for viral DNA synthesis that is not encoded by herpes viruses, yet members of the ␣, ␤, and ␥ herpes viruses (i.e., HSV-1, cytomegalovirus, and Epstein-Barr virus) all have been reported to require this enzyme for viral DNA synthesis (13)(14)(15)(16).…”

Section: H Erpes Simplex Virus 1 (Hsv-1) Encodes At Least 84 Uniquementioning

confidence: 99%

Herpes simplex virus 1 activates cdc2 to recruit topoisomerase IIα for post-DNA synthesis expression of late genes

Advani

Weichselbaum

Roizman

2003

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

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A subset (␥2) of late herpes simplex virus 1 genes depends on viral DNA synthesis for its expression. For optimal expression, a small number of these genes, exemplified by U S11, also requires two viral proteins, the ␣ protein infected cell protein (ICP) 22 and the protein kinase U L13. Earlier we showed that UL13 and ICP22 mediate the stabilization of cdc2 and the replacement of its cellular partner, cyclin B, with the viral DNA polymerase processivity factor U L42. Here we report that cdc2 and its new partner, UL42, bind a phosphorylated form of topoisomerase II␣. The posttranslational modification of topoisomerase II␣ and its interaction with cdc2-UL42 proteins depend on ICP22 in infected cells. Although topoisomerase II is required for viral DNA synthesis, ICP22 is not, indicating a second function for topoisomerase II␣. The intricate manner in which the virus recruits topoisomerase II␣ for post-DNA synthesis expression of viral genes suggests that topoisomerase II␣ also is required for untangling concatemeric DNA progeny for optimal transcription of late genes.H erpes simplex virus 1 (HSV-1) encodes at least 84 unique ORFs. Its genes are expressed in a coordinately regulated, sequentially ordered manner (1, 2). ␣ genes are expressed first, and their products enable the expression of ␤ (early) and ␥ (late) genes. The latter genes are classified further as ␥ 1 or ␥ 2 genes. Whereas ␥ 2 gene expression requires viral DNA synthesis, the expression of ␥ 1 is enhanced by but is not totally dependent on viral DNA synthesis. Studies have shown that primary human cell strains and some animal cell lines accumulate grossly reduced amounts of a subset of ␥ 2 proteins exemplified by the products of U S 11, U L 38, or U L 41 after infection with mutants lacking the genes encoding infected cell protein (ICP) 22 or the U L 13 protein kinase (3, 4). An apparent involvement of cellular factors in the expression of this subset of viral genes emerged from studies of cell cycle proteins. In these studies it was noted that the cyclin-dependent kinase cdc2 (cdk1) was posttranslationally modified, stabilized, and activated 4-12 h after infection (5). Concurrently, cyclin B, a partner of cdc2, was degraded. Mapping studies with viral mutants revealed that both the posttranslational modification of cdc2 and the degradation of cyclin B depended on the presence of ICP22 and U L 13 protein kinase. Further studies reinforced the apparent connection between the phenotype of mutant viruses from which either ␣22 or U L 13 mutants were deleted and the activation of cdc2 in infected cells. Thus cells transfected with a dominant negative (dn) mutant of cdc2 and infected with wild-type virus expressed representative ␣, ␤, and ␥ 1 proteins but failed to express the ␥ 2 U S 11 protein (6). These studies linked the stabilization of cdc2 with the expression of the U S 11 gene and indicated that ICP22 and U L 13 mediate the accumulation of the subset of ␥ 2 proteins represented by U S 11 by inducing the posttranslational modification of cdc2, but t...

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“…The ␣-form localizes to the inside of nucleoli (6) and clusters at centromeric regions (8), whereas the ␤-isoenzyme shows a reticular pattern in the vicinity but mostly outside of nucleoli (6). In mitosis the ␤-isoenzyme diffuses away from the chromatin, whereas the ␣-isoenzyme becomes up-regulated (9 -11) and binds tightly to the centromeres and the axes of the chromosome arms (5,6,12), where it displays a dynamic pattern, which changes as cells progress through mitosis (13). There are indications that the ␣-isoenzyme in its chromosome-bound state is mostly catalytically inactive, whereas the ␤-isoenzyme sustains a diffusible type II topoisomerase activity throughout the cell cycle (6).…”

mentioning

confidence: 99%

Essential Mitotic Functions of DNA Topoisomerase IIα Are Not Adopted by Topoisomerase IIβ in Human H69 Cells

Grue¹,

Gräßer²,

Sehested³

et al. 1998

Journal of Biological Chemistry

123

111

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Unique functions of mammalian DNA-topoisomerases II␣ and -␤ are suggested by their distinct cellular distribution and chromatin binding at mitosis. Here, we studied H69-VP cells that, due to a homozygous mutation, express topoisomerase II␣ mostly outside the nucleus. In these cells topoisomerase II␤ showed a normal nuclear localization. However, at mitosis it diffused away from the chromatin despite the nuclear lack of the ␣-isoform. 80% of these cells performed chromosome condensation and disjunction with the aid of cytosolic topoisomerase II␣, which bound to the mitotic chromatin with low affinity. However, the genotype of these cells was highly polyploid indicating an increased rate of non-disjunction. In 20% of the mutant cells neither topoisomerase II isoform was bound to the mitotic chromatin, which appeared as an unstructured DNA spheroid unable to undergo disjunction and cytokinesis. Parental H69 cells expressing topoisomerase II␣ inside the nucleus exhibited high affinity binding of the enzyme to the mitotic chromatin. Their genotype was mostly diploid and stable. We conclude (i) that high affinity chromatin binding of topoisomerase II␣ is essential for chromosome condensation/disjunction and (ii) that topoisomerase II␤ does not adopt these functions.

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DNA topoisomerase II alpha is the major chromosome protein recognized by the mitotic phosphoprotein antibody MPM-2.

Cited by 157 publications

References 38 publications

In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites

In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites

Herpes simplex virus 1 activates cdc2 to recruit topoisomerase IIα for post-DNA synthesis expression of late genes

Essential Mitotic Functions of DNA Topoisomerase IIα Are Not Adopted by Topoisomerase IIβ in Human H69 Cells

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