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| Item Type: | Article |
|---|---|
| Title: | Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations |
| Creators Name: | Dellino, G.I., Palluzzi, F., Chiariello, A.M., Piccioni, R., Bianco, S., Furia, L., De Conti, G., Bouwman, B.A.M., Melloni, G., Guido, D., Giacò, L., Luzi, L., Cittaro, D., Faretta, M., Nicodemi, M., Crosetto, N. and Pelicci, P.G. |
| Abstract: | It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5' splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main predictor and determinant of DSBs. Damaged introns with paused Pol II-pS5, TOP2B and XRCC4 are enriched in translocation breakpoints, and map at topologically associating domain boundary-flanking regions showing high interaction frequencies with distal loci. Thus, in unperturbed growth conditions, release of paused Pol II at specific loci and chromatin territories favors DSB formation, leading to chromosomal translocations. |
| Keywords: | Cultured Cells, DNA Repair, Double-Stranded DNA Breaks, Etoposide, Flow Cytometry, Fluorescent Antibody Technique, Genetic Enhancer Elements, Genetic Loci, Genetic Promoter Regions, Genomics, Introns, Neoplasms, Neoplastic Gene Expression Regulation, RNA Polymerase II, RNA Splice Sites, Topoisomerase Inhibitors, Transcription Initiation Site, Tumor Cell Line, Animals |
| Source: | Nature Genetics |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Volume: | 51 |
| Number: | 6 |
| Page Range: | 1011-1023 |
| Date: | June 2019 |
| Official Publication: | https://doi.org/10.1038/s41588-019-0421-z |
| PubMed: | View item in PubMed |
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