Molecular and Structural Transactions at Human DNA Replication Origins

Falaschi, Arturo; Abdurashidova, G.G.; Sandoval, Oscar; Radulescu, Sorina; Biamonti, Giuseppe; Riva, Silvano

doi:10.4161/cc.6.14.4495

Cited by 29 publications

(44 citation statements)

References 57 publications

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“…There are six human topoisomerase enzymes [18] and three of them, topoisomerase I, topoisomerase IIα and topoisomerase IIβ, have significant involvement in cancer and cancer chemotherapy [19]. The topoisomerase I enzyme nicks and rejoins one strand of the duplex DNA, and topoisomerase II enzyme transiently breaks and closes double-stranded DNA [20]. The topoisomerase I inhibitors (e.g., topotecan) have been used in patients with recurrent small-cell lung cancer, recurrent malignant gliomas, recurrent childhood brain tumors [21], [22].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

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The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

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“…Among the 30 well-mapped human replication origins so far (17), the lamin B2 origin has been studied in detail for its dynamic molecular and topological transactions at nucleotide level (19). However, the chromatin structure and epigenetic regulation of lamin B2 origin by DNA methylation and histone modifications remain obscure.…”

Section: Introductionmentioning

confidence: 99%

The epigenetic control of E-box and Myc-dependent chromatin modifications regulate the licensing of lamin B2 origin during cell cycle

Swarnalatha

Singh

Kumar

2012

Nucleic Acids Research

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Recent genome-wide mapping of the mammalian replication origins has suggested the role of transcriptional regulatory elements in origin activation. However, the nature of chromatin modifications associated with such trans-factors or epigenetic marks imprinted on cis-elements during the spatio-temporal regulation of replication initiation remains enigmatic. To unveil the molecular underpinnings, we studied the human lamin B2 origin that spatially overlaps with TIMM 13 promoter. We observed an early G1-specific occupancy of c-Myc that facilitated the loading of mini chromosome maintenance protein (MCM) complex during subsequent mid-G1 phase rather stimulating TIMM 13 gene expression. Investigations on the Myc-induced downstream events suggested a direct interaction between c-Myc and histone methyltransferase mixed-lineage leukemia 1 that imparted histone H3K4me3 mark essential for both recruitment of acetylase complex HBO1 and hyperacetylation of histone H4. Contemporaneously, the nucleosome remodeling promoted the loading of MCM proteins at the origin. These chromatin modifications were under the tight control of active demethylation of E-box as evident from methylation profiling. The active demethylation was mediated by the Ten-eleven translocation (TET)-thymine DNA glycosylase-base excision repair (BER) pathway, which facilitated spatio-temporal occupancy of Myc. Intriguingly, the genome-wide 43% occurrence of E-box among the human origins could support our hypothesis that epigenetic control of E-box could be a molecular switch for the licensing of early replicating origins.

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“…Furthermore, it was shown that Drosophila melanogaster ORC ( Dm ORC) exhibits mild sequence specificity, but strong preference for negatively supercoiled DNA, suggesting that the topological state of the DNA is a critical factor for origin specification in that organism (15). Recently, topoisomerases I and II (topo I and II) were also found to interact specifically with the human lamin B2 replication origin in a cell-cycle-regulated manner, indicating that the role of DNA topology during pre-RC assembly may be applicable in mammalian genomes as well (16,17). …”

Section: Introductionmentioning

confidence: 99%

Transient dsDNA breaks during pre-replication complex assembly

Rampakakis

Zannis‐Hadjopoulos

2009

Nucleic Acids Research

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Initiation of DNA replication involves the ordered assembly of the multi-protein pre-replicative complex (pre-RC) during G1 phase. Previously, DNA topoisomerase II (topo II) was shown to associate with the DNA replication origin located in the lamin B2 gene locus in a cell-cycle-modulated manner. Here we report that activation of both the early-firing lamin B2 and the late-firing hOrs8 human replication origins involves DNA topo II-dependent, transient, site-specific dsDNA-break formation. Topo IIβ in complex with the DNA repair protein Ku associates in vivo and in vitro with the pre-RC region, introducing dsDNA breaks in a biphasic manner, during early and mid-G1 phase. Inhibition of topo II activity interferes with the pre-RC assembly resulting in prolonged G1 phase. The data mechanistically link DNA topo IIβ-dependent dsDNA breaks and the components of the DNA repair machinery with the initiation of DNA replication and suggest an important role for DNA topology in origin activation.

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Molecular and Structural Transactions at Human DNA Replication Origins

Cited by 29 publications

References 57 publications

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

The epigenetic control of E-box and Myc-dependent chromatin modifications regulate the licensing of lamin B2 origin during cell cycle

Transient dsDNA breaks during pre-replication complex assembly

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