Functional interactions of DNA topoisomerases with a human replication origin

Abdurashidova, G.G.; Radulescu, Sorina; Sandoval, Oscar; Zahariev, Sotir; Danailov, M. B.; Demidovich, Alexander; Santamaría, Laura; Biamonti, Giuseppe; Riva, Silvano; Falaschi, Arturo

doi:10.1038/sj.emboj.7601578

Cited by 48 publications

(49 citation statements)

References 36 publications

(52 reference statements)

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“…This is in agreement with recent data showing that Top1 associates with the ARS305 region and copurifies with the GINS-MCM complex (Gambus et al 2006). However, the situation is somehow different in human cells, as recent observations obtained by treating cells with Top1 and Top2 inhibitors suggest that DNA topoisomerase I interacts with replication origins in M, G1, and G1/S, while DNA topoisomerase II does so in M and G1 (Abdurashidova et al 2007). Following origin firing, the localization of Top1 Figure 6.…”

Section: Top1 and Top2 Associate With Replicating Chromosomal Regionssupporting

confidence: 81%

Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation

Bermejo¹,

Doksani²,

Capra³

et al. 2007

Genes Dev.

144

133

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Supplemental material is available at http://www.genesdev.org. Received March 8, 2007; revised version accepted June 21, 2007. Chromosome replication is coordinated with transcription, recombination, chromatin remodeling, cohesion, and checkpoints. Several events can compromise the integrity of replicating chromosomes, such as misincorporation of dNTPs, DNA damage, interference between replication and transcription, and unscheduled recombination processes. Furthermore, the advancement of replication forks generates tremendous topological constraints that must be solved by DNA topoisomerases, specialized enzymes that act by nicking and closing the DNA strands. A failure to properly coordinate replication fork progression with the topoisomerase-mediated processes that relieve topological constrains may cause fork collapse and double-strand break (DSB) formation.Several studies indicate that DNA topoisomerases catalyze strand passage reactions, thus changing the linkage of DNA molecules (Wang 1996;Champoux 2001), and can alleviate the topological problems generated during DNA replication (Fig. 1A). Unwinding of the DNA duplex by replicative helicases creates a compensatory increase in the intertwining of parental strands (Wang 2002;Postow et al. 2004). The mechanical strain thus generated can be converted into helical overwinding (positive supercoiling) of the unreplicated portions of the DNA ahead of the forks. It has been proposed that this mechanical strain can be also transmitted to replicated DNA by rotation at the replication fork branching point, thus generating intertwining of the daughter duplexes (known as precatenates). Accumulation of positive supercoiling thermodynamically counteracts the action of replicative DNA helicases. The precatenate nodes, if not resolved, would establish a physical link between the sister chromatids that can impede their accurate segregation during mitosis (Champoux and Been

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Section: Top1 and Top2 Associate With Replicating Chromosomal Regionssupporting

confidence: 81%

Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation

Bermejo¹,

Doksani²,

Capra³

et al. 2007

Genes Dev.

144

133

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“…Restructuring and activation of certain promoters require topoisomerase IIelicited DNA breaks (31). Recently, both topoisomerase I and II have been shown to compete with ORC2 and induce ss breaks at the lamin B2 origin of replication in a well orchestrated manner throughout the cell cycle, giving an essential contribution to origin definition; in addition, topoisomerase II appeared to be a permanent resident of a neighboring S/MAR (32).…”

Section: Discussionmentioning

confidence: 99%

Ribonucleoprotein-masked nicks at 50-kbp intervals in the eukaryotic genomic DNA

Székvölgyi¹,

Rákosy²,

Bálint³

et al. 2007

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

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By using a microscopic approach, field inversion single-cell gel electrophoresis, we show that preformed single-strand discontinuities are present in the chromatin of resting and proliferating mammalian and yeast cells. These single-strand breaks are primarily nicks positioned at Ϸ50-kbp intervals throughout the entire genome that could be efficiently labeled in situ by DNA polymerase I holoenzyme but not by Klenow fragment and terminal transferase unless after ribonucleolytic treatments. The RNA molecules involved appear to comprise R-loops, recognized by the S9.6 RNA/DNA hybrid-specific antibody. By using the breakpoint cluster region of the Mixed Lineage Leukemia (MLL) gene as a model, we have found that the number of manifest nicks detected by FISH performed after field inversion single-cell gel electrophoresis depends on epigenetic context, but the difference between germ-line and translocated MLL alleles is abolished by protease treatment. Our data imply that the double-stranded genomic DNA is composed of contiguous rather than continuous single strands and reveal an aspect of higher-order chromatin organization with ribonucleoprotein-associated persistent nicks defining Ϸ50-kbp domains.chromatin loop ͉ RNA/DNA hybrid ͉ translocation T he concept that eukaryotic chromatin is organized into Ϸ30-to 150-kbp units anchored to a ribonucleoprotein-containing structure, the enigmatic nuclear matrix/scaffold, has stemmed from microscopic observations of DNA loops emanating from histone-depleted nuclei (for review, see ref 1). Chromatin appears to bind matrix elements through special, although heterogeneous, DNA sequences, scaffold/matrix attachment regions (S/MARs), that remain attached to the remnants of saltextracted nuclei (nuclear halos) and are thought to represent the boundaries of supercoiled 20-to 150-kbp looped domains (2). Consistent with this model of chromosome architecture, chromatin fragmentation phenomena have been observed that involve the preferential cleavage of DNA, presumably at the bases of loops (3). The global disassembly of chromatin to highmolecular-weight (Ն20-kbp) units also takes place upon alkali denaturation after proteinase digestion (4), at exposure to single-strand (ss)-specific nuclease (5), in the early stage of apoptotic DNA fragmentation (6), as well as in the case of healthy nonapoptotic mammalian and yeast cells upon various protein denaturing treatments (7,8). The DNase I hypersensitivity of mammalian chromatin at every Ϸ50 kbp (9), also detected in the vicinity of certain S/MARs (10), points to the special vulnerability of the DNA at the borders of supernucleosomal units of this size. The above data raise the question whether special base-unpaired secondary structures or perhaps regularly spaced stably maintained ss discontinuities constitute the predilection points of Ϸ50-kbp chromatin fragmentation, delimiting higher-order domains. To tackle this issue, based on the conventional comet assay (11), we have developed a microscopic approach, field inversion single-cell gel el...

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“…In the previous years the presence of ORC, Cdc6 and other proteins on metazoan origins was demonstrated by several groups. 1 In the course of our studies on the proteins belonging to the replicative complexes of the lamin B2 origin, [2][3][4] we searched for possible novel factors through a yeast one-hybrid screen for human proteins binding to that sequence; this search brought to the identification of only three proteins, all orthologues of the product of the Abdominal B gene of Drosophila, namely the HOXA13, HOXC10 and HOXC13 proteins. For two of them (HOXC10 and HOXC13) their ability to bind specifically to the origin sequence in vitro was demonstrated by electrophoretic mobility shift assay and by DNase I footprinting; furthermore, the HOXC10 and HOXC13 proteins were also shown by CAT-assay to interact in vivo with the same origin sequence.…”

Section: Introductionmentioning

confidence: 99%

The homeotic protein HOXC13 is a member of human DNA replication complexes

Comelli

Marchetti²,

Arosio³

et al. 2009

Cell Cycle

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The homeotic (and oncogenic) HOXC13 protein was shown to have an affinity for a DNA fragment corresponding to the sequence covered by the pre-replicative complex of the human lamin B2 replication origin. We show here that HOXC13 is a member of human replicative complexes. Our fluorescent fusion-protein data demonstrate that it co-localizes with replication foci of early-S cells and that this peculiar behaviour is driven by the homeodomain. By ChIP analysis we also show that HOXC13 binds the lamin B2 replication origin and the origins located near the TOP1 and MCM4 genes in asynchronously growing cells, whereas it does not bind these origins in G 0 resting cells, consistently with its involvement in origin function.

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Functional interactions of DNA topoisomerases with a human replication origin

Cited by 48 publications

References 36 publications

Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation

Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation

Ribonucleoprotein-masked nicks at 50-kbp intervals in the eukaryotic genomic DNA

The homeotic protein HOXC13 is a member of human DNA replication complexes

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