Human Topoisomerase IIα is Phosphorylated in a Cell‐Cycle Phase‐Dependent Manner by a Proline‐Directed Kinase

Wells, Nicholas J.; Hickson, Ian D.

doi:10.1111/j.1432-1033.1995.0491e.x

Cited by 22 publications

(9 citation statements)

References 44 publications

(42 reference statements)

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“…Topoisomerase II alpha is phosphorylated on multiple Ser and Thr residues, most of which are located in the C‐terminal domain . Several potential ATM‐dependent or ‐regulated phosphorylation sites (Ser1424, 1466, 1522, and 1524) were reported .…”

Section: Discussionmentioning

confidence: 99%

“…Topoisomerase II alpha is phosphorylated on multiple Ser and Thr residues, most of which are located in the C-terminal domain. (34)(35)(36)(37)(38)(39) Several potential ATM-dependent or -regulated phosphorylation sites (Ser1424, 1466, 1522, and 1524) were reported. (40) Our findings showed phosphorylation of a new target site, Ser1512, induced by DNA damage in an ATMdependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor

et al. 2013

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Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM-dependent manner after DNA damage. In vitro kinase assay and site-directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasiaderived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM-dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low-dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment-associated secondary leukemia following exposure to TOP2 inhibitors. (Cancer Sci 2013; 104: 178-184) A taxia telangiectasia (AT) is an autosomal recessive disorder characterized by a pleiotropic phenotype that includes progressive cerebellar degeneration, immunodeficiency, premature aging, genetic instability, and a high incidence of cancer. Heterozygous carriers also appear to be at increased risk of cancer.(1,2) Cells from AT homozygotes lack multiple cell cycle check points, and this leads to hypersensitivity to double-strand breaks in the DNA. (3,4) DNA topology is controlled and altered by DNA topoisomerases. Topoisomerases are ubiquitous enzymes that resolve topological problems, which arise during the various processes of DNA metabolism including transcription, recombination, replication, and chromosome partitioning during cell division. Topoisomerase I introduces a transient single-strand break into the DNA, passes an intact single strand of DNA through the broken strand, and re-ligates the break. Topoisomerase II (TOP2) makes transient double-strand breaks in one segment of DNA and passes an intact duplex through the broken DNA before resealing the breaks. Human cells express two isoforms of TOP2, topoisomerase II alpha (TOP2A) and topoisomerase II beta (TOP2B). TOP2A is expressed mainly during the S to G 2 ⁄ M phase of the cell cycle and is likely to play a major role in DNA catenation during mitosis. In contrast, TOP2B is expressed constantly throughout the cell cycle. The function of TOP2B is unknown, but the enzyme is speculated to be involved in the metabolism of DNA and ⁄ or RNA. Topoisomerase II alpha is highly phosphorylated, and its enzymatic activity has been postulated to be regulated by ph...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor

et al. 2013

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“…The supercoiling and knotting activities of condensin and Topo II␣ are activated by cellular Cdc2 kinase-induced phosphorylation (28,56). To explore whether BGLF4 can phosphorylate condensin and Topo II␣ directly, recombinant BGLF4 kinase and the kinase-dead mutant K102I were expressed in a recombinant baculovirus system.…”

Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus BGLF4 Kinase Induces Disassembly of the Nuclear Lamina To Facilitate Virion Production

Lee

Huang

Lin³

et al. 2008

J Virol

110

145

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). In this study, we show that BGLF4 interacts with lamin A/C and phosphorylates lamin A protein in vitro. Using a green fluorescent protein (GFP)-lamin A system, we found that Ser-22, Ser-390, and Ser-392 of lamin A are important for the BGLF4-induced disassembly of the nuclear lamina and the EBV reactivation-mediated redistribution of nuclear lamin. Virion production and protein levels of two EBV primary envelope proteins, BFRF1 and BFLF2, were reduced significantly by the expression of GFP-lamin A(5A), which has five Ser residues replaced by Ala at amino acids 22, 390, 392, 652, and 657 of lamin A. Our data indicate that BGLF4 kinase phosphorylates lamin A/C to promote the reorganization of the nuclear lamina, which then may facilitate the interaction of BFRF1 and BFLF2s and subsequent virion maturation. UL kinases of alpha-and betaherpesviruses also induce the disassembly of the nuclear lamina through similar sites on lamin A/C, suggesting a conserved mechanism for the nuclear egress of herpesviruses.Most DNA viruses replicate and assemble their genomes into nucleocapsids in the nuclei of infected cells. To facilitate efficient replication, viruses regulate the nuclear environment by affecting cellular chromatin and nuclear lamina (30,35,40). The nuclear lamina is a thin electron-dense meshwork lining the nucleoplasmic face of the inner nuclear membrane (INM) (14, 20) and provides structural support for the major components of the nuclear envelope (36, 39). The lamina also functions as a transverse scaffold for INM proteins (e.g., emerin and lamin B receptor), chromatin proteins (histone H2A/H2B dimers), and cytoskeleton-interacting proteins (nesprin1/2) (7, 52).The nuclear lamina comprises a series of type V intermediate filaments composed of lamin types A, B1, B2, and C. Types A and C are products of RNA splicing variants of the lmnA transcripts, whereas types B1 and B2 are derived from two other genes, lmnB1 and B2 (15, 22). The INM-associated lamin B layer provides the fundamental structure of the lamina and is essential for the nuclear shape, whereas the lamin A/C layer adjacent to the nucleoplasm has more specialized functions and contributes to nuclear stiffness (7, 23, 52). Similarly to other intermediate filaments, lamins contain globular head and tail domains flanked by a central rod domain (15). The rod domains of two lamin molecules can intertwine to form dimers, whereas regions flanking the head/rod and rod/tail domains potentially interact with other lamin dimers to form longer filaments (45). Physiologically, the nuclear lamina is reorganized dynamically throughout the cell cycle via a mechanism regulated by phosphorylation. Phosphorylation by mitotic Cdc2 kinase at Ser-22, Ser-390, and Ser-392 residues on lamin A/C, or by protein kinase C (PKC) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the INM (11,21,44).The intact meshwork of the nuclear lamina also presents a barrier to most DNA viruses. Upon infection,...

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“…TopoIIα undergoes a myriad of phosphorylations during mitosis, including those catalysed by CDC2 and protein kinase C [6,7]. TopoIIα is in fact the major mitotic chromosomal protein recognized by MPM-2 [8].…”

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confidence: 99%

Mitotic phosphorylation: breaking the balance of power by a tactical retreat

Poon

2007

Biochemical Journal

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Profound changes in the phosphorylation state of many proteins occur during mitosis. It is well established that many of these mitotic phosphorylations are carried out by archetypal mitotic kinases that are activated only during mitosis, shifting the equilibrium of kinases and phosphatases towards phosphorylation. However, many studies have also detailed the phosphorylation of proteins at mitosis by kinases that are constitutively active throughout the cell cycle. In most cases, it is uncertain how kinases and phosphatases that appear to be constitutively active can induce phosphorylations specifically at mitosis. In this issue of the Biochemical Journal, Escargueil and Larsen provide evidence of an interesting alternative mechanism to attain specific mitotic phosphorylation. A mitosis-specific phosphorylation site in DNA topoisomerase IIα, which is recognized by the MPM-2 antibody, is phosphorylated by protein kinase CK2. The authors found that phosphorylation of this site is suppressed during interphase due to competing dephosphorylation by protein phosphatase 2A. Interestingly, protein phosphatase 2A is excluded from the nucleus during early mitosis, allowing CK2 to phosphorylate topoisomerase IIα. It is possible that similar mechanisms are used to regulate the phosphorylation of other proteins.

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Human Topoisomerase IIα is Phosphorylated in a Cell‐Cycle Phase‐Dependent Manner by a Proline‐Directed Kinase

Cited by 22 publications

References 44 publications

Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor

Ataxia telangiectasia mutated‐dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor

Epstein-Barr Virus BGLF4 Kinase Induces Disassembly of the Nuclear Lamina To Facilitate Virion Production

Mitotic phosphorylation: breaking the balance of power by a tactical retreat

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