Topoisomerase I-mediated DNA damage

2001 ◽  
pp. 189-216 ◽  
Author(s):  
Philippe Pourquier ◽  
Yves Pommier
Keyword(s):  
Dna Damage ◽  
Topoisomerase I

scholarly journals The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Luisa Statello ◽  
Mohamad M Ali ◽  
Silke Reischl ◽  
Sagar Mahale ◽  
Subazini Thankaswamy Kosalai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Biology ◽  
Topoisomerase I ◽  
Cell Cycle Checkpoints ◽  
Topoisomerase 1 ◽  
Damage Response ◽  
Promote Cell Survival

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

The Coffee Constituent Chlorogenic Acid Induces Cellular DNA Damage and Formation of Topoisomerase I– and II–DNA Complexes in Cells

2012 ◽  
Vol 60 (30) ◽  
pp. 7384-7391 ◽  
Author(s):  
Estefanía Burgos-Morón ◽  
José Manuel Calderón-Montaño ◽  
Manuel Luis Orta ◽  
Nuria Pastor ◽  
Concepción Pérez-Guerrero ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chlorogenic Acid ◽  
Topoisomerase I ◽  
Dna Complexes ◽  
Cellular Dna ◽  
In Cells

scholarly journals Selective ploidy ablation, a high-throughput plasmid transfer protocol, identifies new genes affecting topoisomerase I-induced DNA damage

2010 ◽  
Vol 21 (3) ◽  
pp. 477-486 ◽  
Author(s):  
R. J. D. Reid ◽  
S. Gonzalez-Barrera ◽  
I. Sunjevaric ◽  
D. Alvaro ◽  
S. Ciccone ◽  
...  
Keyword(s):  
Dna Damage ◽  
High Throughput ◽  
Topoisomerase I ◽  
Plasmid Transfer ◽  
New Genes ◽  
Transfer Protocol

scholarly journals DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

2004 ◽  
Vol 3 (1) ◽  
pp. 82-90 ◽  
Author(s):  
Mobeen Malik ◽  
John L. Nitiss
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Excision Repair ◽  
Dna Strand Breaks ◽  
Dna Topology ◽  
Strand Breaks ◽  
Wide Range ◽  
Dna Strand

ABSTRACT DNA topoisomerases play critical roles in a wide range of cellular processes by altering DNA topology to facilitate replication, transcription, and chromosome segregation. Topoisomerases alter DNA topology by introducing transient DNA strand breaks that involve a covalent protein DNA intermediate. Many agents have been found to prevent the religation of DNA strand breaks induced by the enzymes, thereby converting the enzymes into DNA-damaging agents. Repair of the DNA damage induced by topoisomerases is significant in understanding drug resistance arising following treatment with topoisomerase-targeting drugs. We have used the fission yeast Schizosaccharomyces pombe to identify DNA repair pathways that are important for cell survival following drug treatment. S. pombe strains carrying mutations in genes required for homologous recombination such as rad22A or rad32 (homologues of RAD52 and MRE11) are hypersensitive to drugs targeting either topoisomerase I or topoisomerase II. In contrast to results observed with Saccharomyces cerevisiae, S. pombe strains defective in nucleotide excision repair are also hypersensitive to topoisomerase-targeting agents. The loss of DNA replication or DNA damage checkpoints also sensitizes cells to both topoisomerase I and topoisomerase II inhibitors. Finally, repair genes (such as the S. pombe rad8+ gene) with no obvious homologs in other systems also play important roles in causing sensitivity to topoisomerase drugs. Since the pattern of sensitivity is distinct from that seen with other systems (such as the S. cerevisiae system), our results highlight the usefulness of S. pombe in understanding how cells deal with the unique DNA damage induced by topoisomerases.

Assessing DNA Damage Ex Vivo Induced by Chemotherapy Targeting Topoisomerase Inhibitors in Acute Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4372-4372
Author(s):  
Dorota H. Halicka ◽  
Fevzi M. Ozkaynak ◽  
Karen Seiter ◽  
Malgorzata A. Kajstura ◽  
Delong Liu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dna Damage ◽  
Topoisomerase I ◽  
Ex Vivo ◽  
Leukemic Cell ◽  
Drug Infusion ◽  
H2ax Phosphorylation ◽  
Acute Leukemias ◽  
Histone H2ax ◽  
Number Of Patients

Abstract Our previous experiments on leukemic cell lines demonstrated that the intensity of immunofluorescence (IF) that is proportional to the level of the phosphorylated histone H2AX (γH2AX) reveals the frequency of DNA double-strand breaks (DSBs) in chromatin induced by DNA topoisomerase I and II (topo I and II) inhibitors. The aim of the present study was to explore whether ex vivo assessment of the extent of DNA damage in leukemic blasts induced during chemotherapy is feasible. The long term goal is to develop a rapid assay to assess the effectiveness of chemotherapy early in the course of treatment of leukemia. Mononuclear cells were isolated from blood samples of 1 AML and 10 ALL patients with peripheral blasts, 4 of whom were, at diagnosis, high-risk ALL while 4 were in relapse. The median age of the patients was 17 yrs (2–25 yrs) and all were entered into an anthracycline-containing drug regimen. Samples were collected: prior to drug administration; and, one hour after completion of the drug infusion. The extent of DNA damage was assessed by analysis of histone H2AX phosphorylation occurring at sites of DSBs, which could be detected immunocytochemically and measured by multiparameter flow cytometry in conjunction with DNA content. In the only patient not responding to treatment, one of 4 relapsed ALL patients, there was no induction of DSBs and no activation of ATM. In all patients phosphorylation of ATM appeared to be strongly linked to induction of DSBs after treatment targeting topo inhibitors. In a pilot study of 3 adult patients with acute leukemia (two AML and one ALL in relapse) treated with the topo II inhibitor Mitoxantrone (MTX), ATM activation was strongly linked to induction of DSBs 1 h post drug infusion. ATM activation and induction of DSBs was several times higher in two adult responders in comparison to one non responder to therapy. A new approach to detect DNA damage in leukemic cell by flow cytometry using gating strategy which combines CD45 expression on the cell surface with side scatter (SS) is being developed and was applied in 5 cases. This approach will be useful when the proportion of blasts in peripheral blood is low. Although the number of patients is very small in this study, the results suggest that a cytometric assay that reveals the extent of DNA damage based on detection of H2AX phosphorylation during induction therapy targeting topo I and II inhibitors may provide an early prognostic marker.

scholarly journals The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor

2005 ◽  
Vol 25 (17) ◽  
pp. 7889-7899 ◽  
Author(s):  
Ada Collura ◽  
Joel Blaisonneau ◽  
Giuseppe Baldacci ◽  
Stefania Francesconi
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Topoisomerase I ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Genetic Material ◽  
Spindle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Replicative Stress

ABSTRACT Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase I, the Chk1 DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G2/M DNA damage checkpoint.

scholarly journals PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage

2014 ◽  
Vol 42 (7) ◽  
pp. 4435-4449 ◽  
Author(s):  
Benu Brata Das ◽  
Shar-yin N. Huang ◽  
Junko Murai ◽  
Ishita Rehman ◽  
Jean-Christophe Amé ◽  
...  
Keyword(s):  
Dna Damage ◽  
Topoisomerase I

scholarly journals Structural and functional interactions of the prostate cancer suppressor protein NKX3.1 with topoisomerase I

2013 ◽  
Vol 453 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Liang-Nian Song ◽  
Cai Bowen ◽  
Edward P. Gelmann
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Topoisomerase I ◽  
Cellular Response ◽  
Peptide Fragments ◽  
The Core ◽  
Tumour Suppressor Protein ◽  
Linker Domain ◽  
In Cells

NKX3.1 (NK3 homeobox 1) is a prostate tumour suppressor protein with a number of activities that are critical for its role in tumour suppression. NKX3.1 mediates the cellular response to DNA damage by interacting with ATM (ataxia telangiectasia mutated) and by activation of topoisomerase I. In the present study we characterized the interaction between NKX3.1 and topoisomerase I. The NKX3.1 homeodomain binds to a region of topoisomerase I spanning the junction between the core and linker domains. Loss of the topoisomerase I N-terminal domain, a region for frequent protein interactions, did not affect binding to NKX3.1 as was shown by the activation of Topo70 (N-terminal truncated topoisomerase I) in vitro. In contrast, NKX3.1 interacts with the enzyme reconstituted from peptide fragments of the core and linker active site domains, but inhibits the DNA-resolving activity of the reconstituted enzyme in vitro. The effect of NKX3.1 on both Topo70 and the reconstituted enzyme was seen in the presence and absence of camptothecin. Neither NKX3.1 nor CPT (camptothecin) had an effect on the interaction of the other with topoisomerase I. Therefore the interactions of NKX3.1 and CPT with the linker domain of topoisomerase I are mutually exclusive. However, in cells the effect of NKX3.1 on topoisomerase binding to DNA sensitized the cells to cellular toxicity and the induction of apoptosis by low doses of CPT. Lastly, topoisomerase I is important for the effect of NKX3.1 on cell survival after DNA damage as topoisomerase knockdown blocked the effect of NKX3.1 on clonogenicity after DNA damage. Therefore NKX3.1 and topoisomerase I interact in vitro and in cells to affect the CPT sensitivity and DNA-repair functions of NKX3.1.

Sign in / Sign up

Export Citation Format

Share Document