TY - JOUR
T1 - Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations
AU - Dellino, Gaetano Ivan
AU - Palluzzi, Fernando
AU - Chiariello, Andrea Maria
AU - Piccioni, Rossana
AU - Bianco, Simona
AU - Furia, Laura
AU - De Conti, Giulia
AU - Bouwman, Britta A.M.
AU - Melloni, Giorgio
AU - Guido, Davide
AU - Giacò, Luciano
AU - Luzi, Lucilla
AU - Cittaro, Davide
AU - Faretta, Mario
AU - Nicodemi, Mario
AU - Crosetto, Nicola
AU - Pelicci, Pier Giuseppe
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-019-0421-z
DO - 10.1038/s41588-019-0421-z
M3 - Article
C2 - 31110352
AN - SCOPUS:85066082844
SN - 1061-4036
VL - 51
SP - 1011
EP - 1023
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -