Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress

Li, Tsai Kun; Chen, Allen Y.; Yu, Chiang; Mao, Yong; Wang, Huimin; Liu, Leroy F.

doi:10.1101/gad.13.12.1553

Cited by 148 publications

(133 citation statements)

References 37 publications

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“…Thus, the engagement of topo II in the formation of the cleavable complex with DNA loop domains may represent an early and reversible step in the pathway leading to the excision of DNA loops during apoptosis. Our results support the recent findings of Li et al (9) in that they demonstrated a rapid and reversible activation of topo II-dependent excision of DNA loop domains during apoptosis in human monoblastic leukemia cells.…”

Section: Discussionsupporting

confidence: 83%

“…In addition, another type of DNA cleavage during apoptosis has been reported to yield a set of the high molecular weight (HMW) 1 DNA fragments of about 50 -100 kb (7). The formation of HMW DNA fragments is widely thought to result from the excision of DNA loop domains at the positions of their attachment to the nuclear matrix (8,9) and is considered to be an initial step in DNA disintegration during apoptosis (7, 10 -12).…”

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confidence: 99%

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The Role of Topoisomerase II in the Excision of DNA Loop Domains during Apoptosis

Solovyan¹,

Bezvenyuk²,

Salminen³

et al. 2002

Journal of Biological Chemistry

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Disintegration of nuclear DNA into high molecular weight (HMW) and oligonucleosomal DNA fragments represents two major periodicities of DNA fragmentation during apoptosis. These are thought to originate from the excision of DNA loop domains and from the cleavage of nuclear DNA at the internucleosomal positions, respectively. In this report, we demonstrate that different apoptotic insults induced apoptosis in NB-2a neuroblastoma cells that was invariably accompanied by the formation of HMW DNA fragments of about 50 -100 kb but proceeded either with or without oligonucleosomal DNA cleavage, depending on the type of apoptotic inducer. We demonstrate that differences in the pattern of DNA fragmentation were reproducible in a cell-free apoptotic system and develop conditions that allow in vitro separation of the HMW and oligonucleosomal DNA fragmentation activities. In contrast to apoptosis associated with oligonucleosomal DNA fragmentation, the HMW DNA cleavage in apoptotic cells was accompanied by down-regulation of caspase-activated DNase (CAD) and was not affected by z-VAD-fmk, suggesting that the caspase/CAD pathway is not involved in the excision of DNA loop domains. We further demonstrate that nonapoptotic NB-2a cells contain a constitutively present nuclease activity located in the nuclear matrix fraction that possessed the properties of topoisomerase (topo) II and was capable of reproducing the pattern of HMW DNA cleavage that occurred in apoptotic cells. We demonstrate that the early stages of apoptosis induced by different stimuli were accompanied by activation of topo II-mediated HMW DNA cleavage that was reversible after removal of apoptotic inducers, and we present evidence of the involvement of topo II in the formation of HMW DNA fragments at the advanced stages of apoptosis. The results suggest that topo II is involved in caspase-independent excision of DNA loop domains during apoptosis, and this represents an alternative pathway of apoptotic DNA disintegration from CAD-driven caspase-dependent oligonucleosomal DNA cleavage.At the higher level of chromatin compaction, nuclear DNA is arranged into loop domains by periodical attachment of the chromatin fiber to the nuclear matrix (1, 2). The domain level of chromatin organization is supported by the interaction of specific DNA sequences, matrix/scaffold attachment regions, with nuclear matrix proteins (3). The chromatin loops represent the basic structural components of higher-order chromatin folding, which is maintained during the cell cycle and in differentiated cells (3-5).Disintegration of nuclear DNA into nucleosome-sized fragments represents a classical manifestation of apoptosis (6). In addition, another type of DNA cleavage during apoptosis has been reported to yield a set of the high molecular weight (HMW) 1 DNA fragments of about 50 -100 kb (7). The formation of HMW DNA fragments is widely thought to result from the excision of DNA loop domains at the positions of their attachment to the nuclear matrix (8, 9) and is considered to be an initial...

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

The Role of Topoisomerase II in the Excision of DNA Loop Domains during Apoptosis

Solovyan¹,

Bezvenyuk²,

Salminen³

et al. 2002

Journal of Biological Chemistry

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“…10 High molecular weight DNA fragmentation is a separable event from oligonucleosomal fragmentation (laddering), may be reversible, at least at an early time after exposure to apoptotic triggers and has been proposed to involve topoisomerase II activity. [11][12][13] Thus these observations link topoisomerase II activity to both a class of therapyrelated leukemia and the earliest chromatin modifications seen in apoptosis.…”

Section: Introductionmentioning

confidence: 98%

Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

et al. 2005

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Exposure to topoisomerase II inhibitors is linked to the generation of leukemia involving translocations of the MLL gene, normally restricted to an 8.3 kbp tract, the breakpoint cluster region (BCR). Using an in vitro assay, apoptotic activators, including radiation and anti-CD95 antibody, trigger site-specific cleavage adjacent to exon 12 within the MLL BCR and promote translocation of the MLL gene in cells that can survive. To explore the mechanism of cleavage and rearrangement in more detail, the entire MLL BCR was placed into the pREP4 episomal vector and transfected into human lymphoblastoid TK6 cells. Episomes containing either the MLL BCR, or deletion constructs of 367 bp or larger, were cleaved at the same position as genomic MLL after exposure to apoptotic stimuli. Further analysis of sequence motifs surrounding the cleaved region of MLL showed the presence of both a predicted nuclear matrix attachment sequence and a potential strong binding site for topoisomerase II, flanking the site of cleavage. Inactivation of topoisomerase II by the catalytic inhibitor merbarone did not inhibit MLL cleavage, suggesting that the initial cleavage step for MLL rearrangement is not mediated by topoisomerase II.

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“…The activated oncogenes induce chromosomal instability through production of ROS because the antioxidant NAC attenuates the karyotypic changes. Reactive oxygen can act directly on DNA to cause chromosomal breaks (Karanjawala et al 2002), or indirectly through activation of topoisomerase (Li et al 1999). Fusion of chromosomal breaks by nonhomologous end joining may generate dicentric chromosomes that can shear randomly between the centromeres during mitosis, resulting in uneven distribution of genetic material to the two daughter cells.…”

Section: Oncogenes Collaborate With Chromosomal Instability During Tumentioning

confidence: 99%

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Woo¹,

Poon²

2004

Genes Dev.

114

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Most cancer cells are aneuploid. The chromosomal instability hypothesis contends that aneuploidy is the catalyst for transformation, whereas the gene mutation hypothesis asserts that cancer is driven by mutations to proto-oncogenes and tumor-suppressor genes, with the aneuploidy a side effect of tumorigenesis. Because genotoxic stress induced by "culture shock" can obscure the transforming potential of exogenous genes, we cultured wild-type and p53 −/− mouse embryo fibroblasts in a more physiological (serum-free) environment. Under these conditions, the cells were immortal and, more importantly, chromosomally stable. Expression of oncogenic H-RasV12 did not induce senescence, but sensitized these cells to p53-dependent apoptosis. In addition, H-RasV12 induced chromosomal instability, as well as accumulation and phosphorylation of p53. Significantly, whereas cells grown under standard conditions could be transformed by coexpression of H-RasV12 and E1A, the chromosomally stable cells were refractory to transformation, as measured by anchorage-independent growth and tumor formation in nude mice. These oncogenes required a third genetic alteration that abolished the p53 pathway to create a permissive environment that promotes rapid chromosomal instability and transformation. Oncogene-induced chromosomal instability and transformation was attenuated by antioxidants. These data indicate that chromosomal instability could be a catalyst for oncogenic transformation, and bring together aspects of the chromosomal instability hypothesis and the gene mutation hypothesis for tumorigenesis.[Keywords: Chromosomal instability; oncogenic Ras; p53; transformation] Supplemental material is available at http://www.genesdev.org.

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Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress

Cited by 148 publications

References 37 publications

The Role of Topoisomerase II in the Excision of DNA Loop Domains during Apoptosis

The Role of Topoisomerase II in the Excision of DNA Loop Domains during Apoptosis

Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

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