Dynamic Effects of Topoisomerase I Inhibition on R-Loops and Short Transcripts at Active Promoters

PloS One
Jessica MarinelloGiovanni Capranico

Abstract

Topoisomerase I-DNA-cleavage complexes (Top1cc) stabilized by camptothecin (CPT) have specific effects at transcriptional levels. We recently reported that Top1cc increase antisense transcript (aRNAs) levels at divergent CpG-island promoters and, transiently, DNA/RNA hybrids (R-loop) in nuclear and mitochondrial genomes of colon cancer HCT116 cells. However, the relationship between R-loops and aRNAs was not established. Here, we show that aRNAs can form R-loops in N-TERA-2 cells under physiological conditions, and that promoter-associated R-loops are somewhat increased and extended in length immediately upon cell exposure to CPT. In contrast, persistent Top1ccs reduce the majority of R-loops suggesting that CPT-accumulated aRNAs are not commonly involved in R-loops. The enhancement of aRNAs by Top1ccs is present both in human colon cancer HCT116 cells and WI38 fibroblasts suggesting a common response of cancer and normal cells. Although Top1ccs lead to DSB and DDR kinases activation, we do not detect a dependence of aRNA accumulation on ATM or DNA-PK activation. However, we showed that the cell response to persistent Top1ccs can involve an impairment of aRNA turnover rather than a higher synthesis rate. Finally, a genome-wide ...Continue Reading

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Citations

Oct 21, 2016·Nature Reviews. Molecular Cell Biology·Yves PommierJohn L Nitiss
Jan 11, 2017·Journal of Medicinal Chemistry·Giovanni CapranicoGiovanni Chillemi
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Aug 1, 2018·Genome Biology·Stefano G ManzoFrederic Chedin
Nov 3, 2020·Nucleic Acids Research·Giulia MigliettaGiovanni Capranico
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Nov 9, 2021·Frontiers in Cell and Developmental Biology·Franciele Faccio BusattoJenifer Saffi

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Methods Mentioned

BETA
PCR
electrophoresis
RNA-Seq
Assay

Software Mentioned

DRIVE
Cufflinks
TopHat
Genome browser
NGSplot
StepOne
Trimmomaticv0
Bowtie2

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