Exon Array Analyses across the NCI-60 Reveal Potential Regulation of TOP1 by Transcription Pausing at Guanosine Quartets in the First Intron
Open Access
- 14 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (6), 2191-2203
- https://doi.org/10.1158/0008-5472.can-09-3528
Abstract
Because topoisomerase 1 (TOP1) is critical for the relaxation of DNA supercoils and because it is the target for the anticancer activity of camptothecins, we assessed TOP1 transcript levels in the 60 cell line panel (the NCI-60) of the National Cancer Institute's anticancer drug screen. TOP1 expression levels varied over a 5.7-fold range across the NCI-60. HCT116 colon and MCF-7 breast cancer cells were the highest expressers; SK-MEL-28 melanoma and HS578T breast carcinoma cells were the lowest. TOP1 mRNA expression was highly correlated with Top1 protein levels, indicating that TOP1 transcripts could be conveniently used to monitor Top1 protein levels and activity in tissues. Assessment of the TOP1 locus by array comparative genomic hybridization across the NCI-60 showed copy numbers ranging from 1.71 to 4.13 and a statistically significant correlation with TOP1 transcript levels (P < 0.01). Further analyses of TOP1 expression on an exon-specific basis revealed that exon 1 expression was generally higher and less variable than expression of the other exons, suggesting some form of transcriptional pausing regulation between exons 1 and 2. Accordingly, we found the presence of multiple evolutionarily conserved potential G-quadruplex–forming sequences in the first TOP1 intron. Physicochemical tests for actual quadruplex formation by several of those sequences yielded quadruplex formation for two of them and duplex formation for one. The observations reported here suggest the hypothesis that there is a conserved negative transcription regulator within intron 1 of the TOP1 gene associated with a quadruplex-prone region. Cancer Res; 70(6); 2191–203Keywords
Other Versions
This publication has 42 references indexed in Scilit:
- Ataxia telangiectasia mutated activation by transcription‐ and topoisomerase I‐induced DNA double‐strand breaksEMBO Reports, 2009
- Topoisomerase levels determine chemotherapy response in vitro and in vivoProceedings of the National Academy of Sciences, 2008
- Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regionsBiochimie, 2008
- A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activityNucleic Acids Research, 2008
- Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genesNucleic Acids Research, 2008
- The NCI60 human tumour cell line anticancer drug screenNature Reviews Cancer, 2006
- Repair of Topoisomerase I‐Mediated DNA DamageProgress in Nucleic Acid Research and Molecular Biology, 2006
- G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcriptionNucleic Acids Research, 2006
- A gene expression database for the molecular pharmacology of cancerNature Genetics, 2000
- Systematic variation in gene expression patterns in human cancer cell linesNature Genetics, 2000