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| Status |
Public on Feb 01, 2008 |
| Title |
Non-Classical Functions of Human Topoisomerase I: Genome-wide and Pharmacological Analyses |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The biological functions of nuclear topoisomerase I (Top1) have been difficult to study because knocking out TOP1 is lethal in metazoans. To reveal the functions of human Top1, we have generated stable Top1siRNA cell lines from colon and breast carcinomas (HCT116-siTop1 and MCF-7-siTop1, respectively). In those cells, Top2 compensates for Top1 deficiency. A prominent feature of the siTop1 cells is genomic instability, with chromosomal aberrations and histone gamma-H2AX foci associated with replication. siTop1 cells also show rDNA and nucleolar alterations, and increased nuclear volume. Genome-wide transcription profiling revealed 55 genes with consistent changes in siTop1 cells. Among them, asparagine synthetase (ASNS) was reduced in siTop1 cells, as it also was in cells with transient Top1 downregulation. Conversely, Top1 complementation increased ASNS, indicating a causal link between Top1 and ASNS expression. Correspondingly, pharmacological profiling showed l-asparaginase hypersensitivity in the siTop1 cells. Resistance to camptothecin, aphidicolin, hydroxyurea and staurosporine, and hypersensitivity to etoposide and actinomycin D demonstrated that Top1, in addition to being the target of camptothecins, also regulates DNA replication, rDNA stability and apoptosis. Overall, our studies demonstrate the pleiotropic nature of human Top1 activities. In addition to its classical DNA nicking-closing functions, Top1 plays critical non-classical roles in genomic stability, gene-specific transcription, and response to various anticancer agents.
Keywords: genetic modification design
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| Overall design |
We are using Affymetrix whole genome array U133 Plus 2, which is a single color microarray platform. For colon experiments, we analyzed 2 different samples as 4 replicates. For breast experiments, we analyzed 2 samples as replicates.
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| Citation(s) |
17875716 |
| Submission date |
Feb 28, 2007 |
| Last update date |
Mar 25, 2019 |
| Contact name |
audrey n player |
| E-mail(s) |
playera@mail.nih.gov
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| Phone |
301 435 3431
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| Fax |
301 402 3134
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| Organization name |
national cancer institute
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| Department |
microarray facility
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| Lab |
microarray
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| Street address |
8717 grovemont circle
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| City |
gaithersburg |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (12)
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| GSM172451 |
siTOP1 HCT116-repeat 1 - mAdbID:83278 |
| GSM172452 |
siTOP1 HCT116-repeat 2 - mAdbID:83279 |
| GSM172453 |
si Control HCT116-repeat 1 - mAdbID:83280 |
| GSM172454 |
si Control HCT116-repeat 2 - mAdbID:83281 |
| GSM172455 |
siTOP1 HCT116-repeat 3 - mAdbID:83282 |
| GSM172456 |
siTOP1 HCT116-repeat 4 - mAdbID:83283 |
| GSM172457 |
si Control HCT116-repeat 3 - mAdbID:83284 |
| GSM172458 |
si Control HCT116-repeat 4 - mAdbID:83285 |
| GSM172459 |
siTOP1 MCF7-repeat 1 - mAdbID:83286 |
| GSM172460 |
siTOP1 MCF7-repeat 2 - mAdbID:83287 |
| GSM172461 |
si Control MCF7-repeat 1 - mAdbID:83291 |
| GSM172462 |
si Control MCF7-repeat 2 - mAdbID:83292 |
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| Relations |
| BioProject |
PRJNA98165 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE7161_RAW.tar |
62.4 Mb |
(http)(custom) |
TAR (of CEL) |
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