Eukaryotic DNA topoisomerase IIβ

Austin, Caroline A.; Marsh, Katherine L.

doi:10.1002/(sici)1521-1878(199803)20:3<215::aid-bies5>3.0.co;2-q

Cited by 233 publications

(186 citation statements)

References 70 publications

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“…topo II␣ and topo II␤ in mouse are encoded by separate genes to form Ϸ1,530-and Ϸ1,620-residue proteins, respectively. These share up to 78% sequence homology at their N-terminal three-quarters but only 34% at their C-terminal quarter (23). Our sequence analysis did not detect significant amino acid identities between RHL1 and topo II␤ (Fig.…”

Section: Hyp7 Is Essential For Successive Endocycles Beyond 8cmentioning

confidence: 70%

RHL1 is an essential component of the plant DNA topoisomerase VI complex and is required for ploidy-dependent cell growth

Sugimoto‐Shirasu

Roberts

Stacey

et al. 2005

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

107

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How cells achieve their final sizes is a pervasive biological question. One strategy to increase cell size is for the cell to amplify its chromosomal DNA content through endoreduplication cycles. Although endoreduplication is widespread in eukaryotes, we know very little about its molecular mechanisms. Successful progression of the endoreduplication cycle in Arabidopsis requires a plant homologue of archaeal DNA topoisomerase (topo) VI. To further understand how DNA is endoreduplicated and how this process is regulated, we isolated a dwarf Arabidopsis mutant, hyp7 (hypocotyl 7), in which various large cell types that in the wild type normally endoreduplicate multiple times complete only the first two rounds of endoreduplication and stall at 8C. HYP7 encodes the RHL1 (ROOT HAIRLESS 1) protein, and sequence analysis reveals that RHL1 has similarity to the C-terminal domain of mammalian DNA topo II␣, another type II topo that shares little sequence homology with topo VI. RHL1 shows DNA binding activity in vitro, and we present both genetic and in vivo evidence that RHL1 forms a multiprotein complex with plant topo VI. We propose that RHL1 plays an essential role in the topo VI complex to modulate its function and that the two distantly related topos, topo II and topo VI, have evolved a common domain that extends their function. Our data suggest that plant topo II and topo VI play distinct but overlapping roles during the mitotic cell cycle and endoreduplication cycle.endoreduplication ͉ hypocotyl ͉ root hairless T he control of cell size is a highly regulated process with inputs from genetic, hormonal, and environmental cues. Yeast and mammalian cells usually only double their size during their development; therefore, a key question in their size control is how proliferating cells coordinate cell growth and cell division to maintain size homeostasis. Yeast and many mammalian cells have a cell size checkpoint mechanism in which cells divide only when they reach a critical size (1), whereas some mammalian cells may control their size through extracellular signals (2). Although plant cells also double their cell size during proliferation, they commonly undergo an additional, massive (sometimes Ͼ1,000-fold), postmitotic cell enlargement. Such a large increase in volume is driven by a combination of production of new cytoplasmic mass and cell expansion (driven by water uptake and vacuolar growth), but little is known about the underlying mechanisms involved. Recent genetic evidence strongly supports the classical ''karyoplasmic ratio'' theory that one mechanism to increase cell size is by increasing the ploidy level within a cell, for example through endoreduplication, defined as the amplification of chromosomal DNA without corresponding cell division (3). Several mutants and transgenic plants that have aberrant levels of endoreduplication have been isolated and have led to the identification of key regulators of the endoreduplication cycle or endocycle (3-7). How these regulators control downstream events, however, rem...

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Section: Hyp7 Is Essential For Successive Endocycles Beyond 8cmentioning

confidence: 70%

RHL1 is an essential component of the plant DNA topoisomerase VI complex and is required for ploidy-dependent cell growth

Sugimoto‐Shirasu

Roberts

Stacey

et al. 2005

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

107

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“…Humans encode two isoforms of topoisomerase II, R and (34)(35)(36)(37)(38)(39)(40)(41)(42). While these two isoforms display similar enzymological properties, they differ significantly in their physiology and cellular functions.…”

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confidence: 99%

Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ

2007

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Bioflavonoids are human dietary components that have been linked to the prevention of cancer in adults and the generation of specific types of leukemia in infants. While these compounds have a broad range of cellular activities, many of their genotoxic effects have been attributed to their actions as topoisomerase II poisons. However, the activities of bioflavonoids against the individual isoforms of human topoisomerase II have not been analyzed. Therefore, we characterized the activity and mechanism of action of three major classes of bioflavonoids, flavones, flavonols, and isoflavones, against human topoisomerase IIR and II . Genistein was the most active bioflavonoid tested and stimulated enzymemediated DNA cleavage ∼10-fold. Generally, compounds were more active against topoisomerase II . DNA cleavage with both enzyme isoforms required a 5-OH and a 4′-OH and was enhanced by the presence of additional hydroxyl groups on the pendant ring. Competition DNA cleavage and topoisomerase II binding studies indicate that the 5-OH group plays an important role in mediating genistein binding, while the 4′-OH moiety contributes primarily to bioflavonoid function. Bioflavonoids do not require redox cycling for activity and function primarily by inhibiting enzyme-mediated DNA ligation. Mutagenesis studies suggest that the TOPRIM region of topoisomerase II plays a role in genistein binding. Finally, flavones, flavonols, and isoflavones with activity against purified topoisomerase IIR and II enhanced DNA cleavage by both isoforms in human CEM leukemia cells. These data support the hypothesis that bioflavonoids function as topoisomerase II poisons in humans and provide a framework for further analysis of these important dietary components.

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“…Topoisomerase II is a nuclear enzyme that is known to be involved in many cellular processes including replication, transcription, sister chromatid decatenation, and as such is crucial for cell survival (Austin and Marsh, 1998). Currently, many antineoplastic drugs such as etoposide and amsacrine are being used clinically as they stabilise the ternary complex and block the normal religation of the cleaved DNA by the enzyme, resulting in a high level of DSB causing cells to undergo apoptosis, or formation of translocations (Felix et al, 2006).…”

mentioning

confidence: 99%

A role for topoisomerase IIα in the formation of radiation-induced chromatid breaks

2008

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Chromatid breaks in cells exposed to low dose irradiation are thought to be initiated by DNA double-strand breaks (DSB), and the frequency of chromatid breaks has been shown to increase in DSB rejoining deficient cells. However, the underlying causes of the wide variation in frequencies of G2 chromatid breaks (or chromatid 'radiosensitivity') in irradiated T-lymphocytes from different normal individuals and cancer cases are as yet unclear. Here we report evidence that topoisomerase IIa expression level is a factor determining chromatid radiosensitivity. We have exposed the promyelocytic leukaemic cell line (HL60) and two derived variant cell lines (MX1 and MX2) that have acquired resistance to mitoxantrone and low expression of topoisomerase II a, to low doses of g-radiation and scored the induced chromatid breaks. Chromatid break frequencies were found to be significantly lower in the variant cell lines, compared with their parental HL60 cell line. Rejoining of DSB in the variant cell lines was similar to that in the parental HL60 strain. Our results indicate the indirect involvement of topoisomerase IIa in the formation of radiation-induced chromatid breaks from DSB, and suggest topoisomerase IIa as a possible factor in the inter-individual variation in chromatid radiosensitivity. British Journal of Cancer (2008) Human response to low doses of ionising radiation shows a wide variation as exemplified by the different frequencies of radiationinduced chromatid breaks observed in metaphase chromosomes in phytohaemagglutinin-stimulated peripheral blood T-lymphocytes (PBL) from different normal individuals and sporadic cancer cases, and elevated frequencies of such chromatid breaks have been linked to cancer susceptibility (Scott et al, 1994(Scott et al, , 1996Roberts et al, 1999;Baria et al, 2001Baria et al, , 2002Buchholz and Wu, 2001;Riches et al, 2001;Papworth et al, 2001;Smart et al, 2003;Baeyens et al, 2002Baeyens et al, , 2005. Using a short time interval (1-2 h) between radiation exposure and sampling, the metaphase cells (blocked with colcemid) collected are those that were in the G2-phase of the cell cycle at the time of exposure and show frequent chromatid breaks (discontinuities or terminal deletions) that have been shown to be induced as a linear function of radiation dose (Bryant, 1998).Cell-cycle arrest is a factor that could possibly influence observed frequencies of chromatid breaks, and at least one study of human tumour cell lines in vitro (Schwartz et al, 1996) reports an inverse relationship between mitotic inhibition and chromatid break frequency. Also, using premature chromosome condensation (PCC) in G2-phase cells with phosphatase inhibitor calyculin, G2 cells were distinguished from normal mitotic metaphases by their split centromeres and by the loss of centromeric constriction (Terzoudi et al, 2005). Using this feature of calyculin-induced PCC to distinguish G2 cells from mitotic metaphase cells, these authors reported that cells from individuals with ataxia telangiectasia (A -T), a homozy...

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Eukaryotic DNA topoisomerase IIβ

Cited by 233 publications

References 70 publications

RHL1 is an essential component of the plant DNA topoisomerase VI complex and is required for ploidy-dependent cell growth

RHL1 is an essential component of the plant DNA topoisomerase VI complex and is required for ploidy-dependent cell growth

Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ

A role for topoisomerase IIα in the formation of radiation-induced chromatid breaks

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