Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Gaetano Ivan Dellino, Fernando Palluzzi, Andrea Maria Chiariello, Rossana Piccioni, Simona Bianco, Laura Furia, Giulia De Conti, Britta A.M. Bouwman, Giorgio Melloni, Davide Guido, Luciano Giacò, Lucilla Luzi, Davide Cittaro, Mario Faretta, Mario Nicodemi, Nicola Crosetto, Pier Giuseppe Pelicci

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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.

Original languageEnglish
Pages (from-to)1011-1023
Number of pages13
JournalNature Genetics
Volume51
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

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ASJC Scopus subject areas

  • Genetics

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