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Release of paused RNA-Polymerase II at specific introns and chromatin domains favors spontaneous DNA double strand break formation and predicts cancer translocations [ChIP-seq & BLISS]

ABSTRACT: Transcriptional activation leads to transient accumulation of DNA Double Strand Breaks (DSBs), which might promote formation of chromosomal translocations. We report here the genomic distribution of DSBs in non-transformed mammary cells grown under unperturbed conditions, using genome-wide Breaks Labeling In Situ and Sequencing (BLISS). We found thousands of high-confidence DSBs, which were enriched at the promoters of a subset of moderately- to highly-transcribed genes (fragile promoters) and co-localized with Topoisomerase II beta. Analyses of DSB-predictive features identified gene length and paused RNA Polymerase II, but not transcription, as critical factors (84% prediction accuracy). Analyses of DSB signaling and repair factors showed high levels of XRCC4, but not of gammaH2AX and NBS1, and no RAD51. Finally, the observed DSBs were predictive of a significant fraction of the recurrent translocations found in human breast cancers. These data suggest that, in normal cells, basal transcription from a specific class of promoters entails accumulation of TOP2B, leading to unresolved DSBs and increased probability of chromosomal translocations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93038 | GEO | 2019/03/12

REPOSITORIES: GEO

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Release of paused RNA-Polymerase II at specific introns and chromatin domains favors spontaneous DNA double strand break formation and predicts cancer translocations [RNA-seq]

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