Disease relevance of TOP1

• The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion [1].
• Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly, and mild anemia [2].
• The breast cancer cell line ZR-75-1, the most sensitive to CPT, was completely defective in CPT-induced TOP1 down-regulation, whereas the breast cancer cell line BT474, the least sensitive to CPT, exhibited effective CPT-induced TOP1 down-regulation [3].
• Among the breast and colorectal cancer cell lines, there was a general correlation between the extent of CPT-induced TOP1 down-regulation and CPT resistance [3].
• This abnormality has been observed primarily in therapy-related leukemias, and TOP1/NUP98 transcripts have not been demonstrated [4].

Psychiatry related information on TOP1

• The cells of an ataxia-oculomotor apraxia type 1 (AOA1) patient, homozygous for a new aprataxin mutation (T739C), were treated with camptothecin, an inhibitor of DNA topoisomerase I which induces DNA single-strand breaks [5].

High impact information on TOP1

• Histone deacetylase interacts directly with DNA topoisomerase II [6].
• Vaccinia DNA topoisomerase breaks and rejoins DNA strands through a DNA-(3'-phosphotyrosyl)-enzyme intermediate [7].
• Rapid induction of c-fos transcription reveals quantitative linkage of RNA polymerase II and DNA topoisomerase I enzyme activities [8].
• The functional association between DNA topoisomerase I and gene activity has been analyzed using the tightly regulated c-fos proto-oncogene, which undergoes rapid transitions between active and inactive states of transcription [8].
• A type II DNA topoisomerase (topollmt), purified to near homogeneity from the trypanosomatid C. fasciculata has been shown to be localized to the single mitochondrion of these kinetoplastid protozoa [9].

Chemical compound and disease context of TOP1

• HTLV-1 tax oncoprotein binds to DNA topoisomerase I and inhibits its catalytic activity [10].
• Coincubation with 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl) polymerase, potentiated CPT toxicity in the resistant lines alone, without affecting CPT: TOP1 interactions [11].
• Sequence identity comparisons between eukaryotic DNA topoisomerase II and bacterial gyrase (bacterial DNA topoisomerase II) indicate that the position of the common mutation observed in mAMSA-resistant human TOP2 corresponds to that of the point mutation nal-31 in the Escherichia coli gyrase B gene, which confers resistance to nalidixic acid [12].
• Doxorubicin and gamma rays increase the level of DNA topoisomerase IIalpha in nuclei of normal and xeroderma pigmentosum fibroblasts [13].
• We have previously shown that treatment of human glioma U87-MG cells expressing wild-type p53 with a DNA topoisomerase II inhibitor, etoposide resulted in ceramide-dependent apoptotic cell death [14].

Biological context of TOP1

• The chromosomal location of the gene has been mapped to the long arm of chromosome 20, in the region q12-13.2, by hybridization of a radioactively labeled TOP1 cDNA probe to human metaphase chromosomes and to a panel of rodent-human somatic hybrids retaining overlapping subsets of human chromosomes [15].
• These results indicate that NUP98 is a recurrent target in therapy-related malignancies, and that TOP1 is a previously unrecognized target for chromosomal translocations [1].
• The 26S proteasome inhibitor MG132 was shown to inhibit CPT-induced down-regulation of TOP1 in BT474 cells and selectively sensitized BT474 but not ZR-75-1 cells to CPT-induced cytotoxicity and apoptosis [3].
• In an effort to identify potential regulators of TOP1 activity, the transcriptional activity of a TOP1 pseudogene in chromosome 1 was studied [16].
• In the aggregate, these results suggest that CPT-induced down-regulation of TOP1 could be an important parameter for determining CPT sensitivity/resistance in tumor cells [3].

Anatomical context of TOP1

• Using truncated versions that direct BTBD2 and TOP1 to the same cellular compartment, either the nucleus or the cytoplasm, co-localization was demonstrated in co-transfected Hela cells [17].
• Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells [18].
• During our search for additional cellular targets of Tax using a yeast two-hybrid screening system, we isolated a cDNA encoding human DNA topoisomerase I. Tax was demonstrated to bind to topoisomerase I in vitro, and the Tax-topoisomerase I complex was also detected in HTLV-1-infected T-cells by immunoprecipitation [10].
• DNA topoisomerase I and II expression in drug resistant germ cell tumours [19].
• The expression of DNA topoisomerase I and II alpha were therefore assessed immunohistochemically in a range of testicular tumours, especially those with persistent malignant elements on retroperitoneal lymph node dissection [19].

Associations of TOP1 with chemical compounds

• Reduced disease-free survival, but not reduced overall survival, was associated with high expression of TOP1 (P = 0.035) and TFAP2C (P = 0.035) [20].
• Top1 inhibitors damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3'-end of the broken DNA [21].
• Sequence analyses of the top1 cDNA from CEM/C2 identified mutations corresponding to two amino acid substitutions, Met370Thr and Asn722Ser [22].
• DNA-topoisomerase I has been implied in RNA splicing because it catalyzes RNA strand transfer and activates serine/arginine-rich RNA-splicing factors by phosphorylation [23].
• The expression of topors is induced by exposure to the genotoxic reagents cisplatin and camptothecin, a DNA topoisomerase I inhibitor [24].

Physical interactions of TOP1

• DNA topoisomerase IIalpha interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution [25].
• MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site [26].
• We now report that cdc2 kinase forms stable molecular complexes with the nuclear enzyme DNA topoisomerase II, which is associated with marked stimulation of both DNA binding and catalytic activity of topoisomerase II, albeit in a phosphorylation-independent manner [27].
• Therefore, stabilization of the DNA-topoisomerase cleavable complexes may be essential in the selectivity of cell kill during S phase [28].
• In preclinical studies, synergy was observed between tumor necrosis factor-alpha (TNF-alpha) and agents that interact with DNA topoisomerase II, such as actinomycin D (Act D) [29].

Enzymatic interactions of TOP1

• Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha, which is recognized by the 3F3/2 phosphoepitope antibody [30].

Regulatory relationships of TOP1

• Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity essentially left unaltered the growth-promoting and leukemogenic effects of NUP98-TOP1 [2].
• The NUP98-DDX10 fusion transcript may promote the development of secondary hematological malignancies caused by DNA-topoisomerase II inhibitors through aberrant nucleocytoplasmic transport and/or alteration in ribosome assembly [31].
• The RNA-splicing factor PSF/p54 controls DNA-topoisomerase I activity by a direct interaction [23].
• Assessment of ATM phosphorylation on Ser-1981 induced by DNA topoisomerase I and II inhibitors in relation to Ser-139-histone H2AX phosphorylation, cell cycle phase, and apoptosis [32].
• PSF/p54(nrb) stimulates "jumping" of DNA topoisomerase I between separate DNA helices [33].

Other interactions of TOP1

• Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA [34].
• As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced [1].
• Human (h) DNA topoisomerase I has been identified as a major SUMO1 target in camptothecin-treated cells [35].
• A TaqI RFLP at the human TOP1 pseudogene locus on chromosome 22q11.2-13.1 (TOP1P2) [36].
• By using primers unique to the TOP1 pseudogene, strand-specific polymerase chain reaction analysis of HeLa RNA amplified products from at least two transcripts oriented in the antisense direction of TOP1 mRNA [16].

Analytical, diagnostic and therapeutic context of TOP1

• Genomic XL PCR did not amplify the reciprocal TOP1/NUP98, nor was this chimera expressed, as expected from the cytogenetic finding [37].
• Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1 [38].
• Reverse transcriptase polymerase chain reaction revealed the NUP98-TOP1 fusion transcript [39].
• Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites [40].
• These results suggest that NUP98 is a recurrent target for therapy-related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations [38].

References