Nuclear Distribution of Human DNA Topoisomerase IIβ: A Nuclear Targeting Signal Resides in the 116-Residue C-Terminal Tail

Cowell, Ian G.; Willmore, Elaine; Chalton, DA; Kl, Marsh; Jazrawi, Elen; Fisher, L. Mark; Austin, Caroline A.

doi:10.1006/excr.1998.4150

Cited by 38 publications

(34 citation statements)

References 30 publications

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“…For instance, the C-terminal domain of topo II␣ has been shown to carry multiple NLSs that function in mammalian cells (34); topo II␤ appears to do so as well (35). Interestingly, the NLSs in topo II␣ do not have equal potency in directing the enzyme into the nucleus (34).…”

Section: Discussionmentioning

confidence: 99%

A Novel Nuclear Localization Signal in Human DNA Topoisomerase I

Mo¹,

Wang²,

Beck³

2000

Journal of Biological Chemistry

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DNA topoisomerase (topo) I is a nuclear enzyme that plays an important role in DNA metabolism. Based on conserved nuclear targeting sequences, four classic nuclear localization signals (NLSs) have been proposed at the N terminus of human topo I, but studies with yeast have suggested that only one of them (amino acids (aa) 150 -156) is sufficient to direct the enzyme to the nucleus. In this study, we expressed human topo I fused to enhanced green fluorescent protein (EGFP) in mammalian cells and demonstrated that whereas aa 150 -156 are sufficient for nuclear localization, the nucleolar localization requires aa 157-199. More importantly, we identified a novel NLS within aa 117-146. In contrast to the classic NLSs that are rich in basic amino acids, the novel NLS identified in this study is rich in acidic amino acids. Furthermore, this novel NLS alone is sufficient to direct not only EGFP into the nucleus but also topo I; and the EGFP⅐topo I fusion driven by the novel NLS is as active in vivo as the wild-type topo I in response to the topo I inhibitor topotecan. Together, our results suggest that human topo I carries two independent NLSs that have opposite amino acid compositions.

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Section: Discussionmentioning

confidence: 99%

A Novel Nuclear Localization Signal in Human DNA Topoisomerase I

Mo¹,

Wang²,

Beck³

2000

Journal of Biological Chemistry

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“…VPA (Sigma) was added to cultures at the concentrations indicated in the text. Rabbit polyclonal antibodies 18511, 18513, 39 3535 and 30400 were generated in house and their specificity was confirmed by western blotting with whole cell extracts and purified recombinant topoisomerase IIα and β. Anti topoisomerase IIβ mab H-8 was from Santa Cruz, mouse MAB antifibrillarin 18380 and anti-HP1β rat MAB MAC353 were from Abcam, mouse anti-γH2AX MAB was from Millipore.…”

Section: Methodsmentioning

confidence: 99%

“…16,54 Previous descriptions of the intranuclear distribution of topoisomerase IIβ have varied in the literature. 39,[43][44][45][46] This may reflect the dynamic nature of topoisomerase IIβ. Topoisomerase IIβ is recruited to the promoters of certain genes during transcriptional activation 25,26 and it is possible that the HDACI-induced redistribution of topoisomerase IIβ reported here reflects the normal dynamic behaviour of the protein during the execution of transcriptional programs, though this possibility remains to be explored.…”

Section: Methodsmentioning

confidence: 99%

“…Topoisomerase be specifically nucleolar. 39,46 The reasons for these differences are not clear, but probably reflect, at least in part, species differences and differences in specimen preparation. Nucleoli of mouse cells for example are associated at their periphery with AT-rich pericentromeric heterochromatin, which clusters in so-called chromocentres around centromeres.…”

Section: Histone Deacetylase Inhibition Redistributes Topoisomerase Imentioning

confidence: 99%

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Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

Cowell¹,

Papageorgiou²,

Padget³

et al. 2011

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“…While it is dispensable for catalytic activity in vitro, this domain contains nuclear localization sequences [49][50][51][52][53][54][55] and sites of phosphorylation [49,[56][57][58]. For many years, the C-terminal domain was thought to contribute little to the enzymatic activity of any type II topoisomerase.…”

Section: Topoisomerase II Domain Structurementioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

358

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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Nuclear Distribution of Human DNA Topoisomerase IIβ: A Nuclear Targeting Signal Resides in the 116-Residue C-Terminal Tail

Cited by 38 publications

References 30 publications

A Novel Nuclear Localization Signal in Human DNA Topoisomerase I

A Novel Nuclear Localization Signal in Human DNA Topoisomerase I

Histone deacetylase inhibition redistributes topoisomerase IIb from heterochromatin to euchromatin

DNA topoisomerase II, genotoxicity, and cancer

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