Length , Splice Sites , and miR-1423 p Transcription Poisoning by Topoisomerase I Is Controlled by Gene

Topoisomerase I (Top1) relaxes DNA supercoiling by forming transient cleavage complexes (Top1cc) upand downstream of transcription complexes. Top1cc can be trapped by carcinogenic and endogenous DNA lesions and by camptothecin, resulting in transcription blocks. Here, we undertook genome-wide analysis of camptothecin-treated cells at exon resolution. RNA samples fromHCT116 and MCF7 cells were analyzed with the Affy Exon Array platform, allowing high-resolution mapping along 18,537 genes. Long genes that are highly expressed were the most susceptible to downregulation, whereas short genes were preferentially upregulated. Along the body of genes, downregulation was most important toward the 30-end and increased with the number of exon– intron junctions. Ubiquitin and RNA degradation-related pathway genes were selectively downregulated. Parallel analysis of microRNA with the Agilent miRNAmicroarray platform revealed that miR-142-3p was highly induced by camptothecin. More than 10% of the downregulated genes were targets of this p53-dependent microRNA. Our study shows the profound impact of Top1cc on transcription elongation, especially at intron–exon junctions and on transcript stability by microRNA miR-142-3p upregulation. Cancer Res; 73(15); 4830–9. 2013 AACR.